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COL. GEORGE WASHINGTON FLOWERS 
MEMORIAL COLLECTION 


TRINITY COLLEGE LIBRARY 
DURHAM, N.C. 


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PERNICIOUS ANEMIA 


Lonpon: 
CAMBRIDGE UNIVERSITY PRESS 





New York: 
G. E. STECHERT & CO. 


Toxyo: 
MARUZEN COMPANY, LTD. 


SHANGHAI: 
EDWARD EVANS & SONS, LTD. 


PERNICIOUS 
ANEMIA 


BY 


BEAUMONT S. CORNELL, M.B. (Tor.) 
Fellow in Duke University 





124380 


DURHAM + NORTH CAROLINA 
DUKE UNIVERSITY PRESS 
OT i7, 


COPYRIGHT 1927 
BY DUKE UNIVERSITY PRESS 


THE SEEMAN PRESS 
DURHAM, N. C. 
Printed in the United States of America 


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FOR NON-MEDICAL READERS 


For seventy years pernicious anemia has remained a 
mysterious and fatal disease. Even persons outside the 
medical profession have become unpleasantly familiar 
with the symptoms,—how it begins with weakness and 
pallor, improves for a time, only to end in death. Within 
the last two or three years, the medical profession has 
been astonished by the discovery of a very satisfactory 
means of treating this hitherto unyielding disease. The 
public is interested in pernicious anemia, and it is with the 
purpose of trying to give lay readers as accurate an idea 
as possible of the disease and its treatment, that this 
chapter is presented. We believe that better understand- 
ing will lead the readers to make sure, by being suitably 
examined, that they themselves are not candidates. 

The most uncontested fact about pernicious anemia has 
always been its invariably fatal termination. Most people 
have seen a case or two occurring perhaps in a relative or 
some associate, and are familiar with the yellowish skin 
and corpse-like pallor and with the extreme weakness so 
pitiable to behold. The word “Anemia” would come to 
the mind of the most inexpert observer and the adjective 
“pernicious”, though quite unscientific, would seem very 
apt indeed. Practically every patient died, usually within a 
period of two or three years, some after four or five 
years and a very few after the lapse of ten years. Once in 
a long while a patient appeared to get well and thus, by 
exception, to prove the rule. 

A very intelligent clergyman once volunteered to the 
writer a remarkable characterization of pernicious ane- 
mia. ““This disease,” he said, “is a type of physical degen- 
eracy which reminds me of the rotting of a hemlock 
knot.” Degeneration: this word has been used over and 


Cv] 


124380 


vi PERNICIOUS ANEMIA 


over again, in many connections, to describe the impres- 
sions of scientific observers. It has not proved to be very 
useful except as a side-track for several train loads of 
ignorance. You may, if you wish, say that the blood of 
these patients degenerates, but you must not overlook the 
fact that certain immutable laws of nature govern even 
the rotting of a hemlock knot. The exact process of dis- 
ease which causes pernicious anemia is just about as 
obscure today as it was in 1822 when a doctor in Scotland 
described the first recorded case. 

The lack of blood is just one of the features. The diges- 
tive organs and the spinal cord are also affected. In normal 
persons the stomach is not only a churn for mixing the 
food, but also a factory for manufacturing a juice which 
has a definite chemical influence on the food. The gastric 
juice is a colorless transparent liquid containing hydro- 
chloric acid and pepsin. In people suffering from perni- 
cious anemia the acid is lacking. It might be surmised, for 
that reason, that the food is not properly digested. One 
might even be led to think that this was the cause of the 
disease. Such an easy solution of the problem is at once 
rendered impossible by the fact that many perfectly 
healthy people go through life without acid in their stom- 
achs. It is apparently true, however, that cases of perni- 
cious anemia are all recruited from among persons having 
no acid in their stomachs. In other words, in order to be 
able to qualify for this most undesirable malady you must 
lack acid in your stomach. Of all persons with achlor- 
hydria (as this lack is named) probably one in ten devel- 
ops pernicious anemia. What causes achlorhydria? We 
do not know, but we think that the condition is hereditary. 
In a few families pernicious anemia runs like a scourge 
among blood relatives all of whom have achlorhydria. 

The spinal cord undergoes degeneration, quite exten- 
sive in many cases. Many of the paths which conduct 
nervous impulses are interrupted and consequently abnor- 


FOR NON-MEDICAL READERS vii 


mal sensations appear in the skin. The chief one is numb- 
ness of the hands and feet. The legs become partly para- 
lyzed and weak. Occasionally the brain is affected in such 
a way that reason departs and the patient becomes mod- 
erately insane. 

It is quite evident therefore that pernicious anemia 
is not merely a disease of the blood. It is a process, rather, 
which involves a great portion of the different organs of 
the body. Even the heart, liver and kidneys are appreci- 
ably affected. 

The first inkling which the patient has of any trouble 
is usually weakness, and weakness alone. A business man 
begins to notice that he tires out in the middle of the day, 
and when he tells his wife, she remarks that he has been 
looking pale or perhaps jaundiced for a few weeks. The 
doctor examines him and finds that he actually has only 
two-fifths of the normal amount of blood. If any indi- 
vidual were suddenly to lose three-fifths of his blood from 
hemorrhage he would be a bed case at once. But where 
the anemia has come on gradually over a number of 
months, his weakness has also developed so slowly that 
he has not at first noticed it. You will at once wonder why 
this man has only two-fifths of his blood. What has hap- 
pened to the rest of it? No matter how closely you ques- 
tion him you will not discover any reason, for he has 
had no hemorrhage at any time. Here, then, is a mystery 
—no pain, no bleeding, no illness, no signs of ill-health— 
but just weakness and lack of blood. If the reader will 
pause to reflect, he will realize that either the blood has 
been destroyed within the body, or else the organs which 
produce blood have become remiss in their function. To 
decide between these alternatives is really the major prob- 
lem of science in connection with this disease. 

Normally blood cells are being constantly formed by 
the marrow of the bones and turned out into the circula- 
tion. Also, blood cells are being constantly disposed of, 


Vili PERNICIOUS ANEMIA 


or destroyed by various organs, when their usefulness is 
at an end. The life of one red blood cell is probably about 
a month. Now the rate of blood production and the rate 
of blood destruction are exactly equal, because the num- 
ber of cells in circulation remains constant. Presented 
with an anemia not caused by hemorrhage, one logically 
concludes that either the rate of blood destruction has 
increased or the rate of blood production has been re- 
duced. We know for sure that the rate of destruction is 
somewhat increased, but we doubt if it has been suffi- 
ciently increased to account for such an anemia. We 
rather believe that a greatly reduced rate of production 
is responsible. 

The red blood cells are very tiny bi-concave discs of 
microscopic dimensions which carry oxygen to all tissues 
of the body. In health they are all practically of the same 
size and shape. In anemias due to hemorrhage they may 
show some degree of variation both in size and shape. In 
pernicious anemia, however, they show most remarkable 
variations in size and shape. Some of the cells are twice 
as wide as normal while others have only half the width 
they should have. 

Some of the smaller cells, instead of preserving their 
disc-like shape, resemble frying pans, dumbells, Indian 
clubs, Grecian urns, water bottles, Indian arrow-heads, 
carrots, etc. It is quite evident that the factory which 
turned out such products as these was in a state of dis- 
organization. Such faulty blood formation is one of the 
best arguments for blaming this anemia upon the bone 
marrow. 

Why, then, does the bone-marrow produce such irregu- 
lar cells and why does it produce fewer cells than it should ? 
That is the fundamental problem of the disease, but it is 
no more fundamental than the question,—why does the 
spinal cord degenerate? There have been at least several 


FOR NON-MEDICAL READERS ix 


dozens of theories advanced in the attempt to explain these 
phenomena. The commonest theory was that some toxin 
or poison arising in the body was simply poisoning the 
spinal cord and the bone-marrow. This “Toxin Theory” 
has held ‘the floor for the past forty years, although 
nobody was able to identify any poison in the body which 
could be responsible, and no one was able to produce true 
pernicious anemia in animals by injecting various poisons. 
Those who held the toxin theory usually supposed that the 
toxin arose from the intestines, but nowadays we are 
beginning to think that our bowels are not quite so harm- 
ful and dispensable as some of our associates would have 
us believe. The commanding position so long held by 
many diseases on toxins, because we know that the poi- 
sons of bacteria are responsible for many diseases. Bacte- 
riology has failed to help solve the problem of pernicious 
anemia, as it has failed in the case of cancer. 

Some scientists believe that bacteriology has ‘done its 
bit” for medicine and everyone is conscious of the grow- 
ing importance of a practically new science,—the study of 
food. Dietetics, or rather nutritional therapy, has caused 
a great change in our attitude toward pernicious anemia. 
Every treatment that has ever been tried,—drugs to no 
end, blood transfusions, surgery,—has failed to alter very 
much the course of the disease. Periods of improvement 
occur without any treatment, and therefore it is difficult 
to judge the effect of any special treatment. 

The fact which we now must take into consideration is 
this,—if a patient with pernicious anemia will eat one- 
half pound of lightly cooked calve’s liver a day, this 
patient will regain such a degree of health that he will, in 
all probability, be able to work and enjoy life. This sounds 
very simple indeed, and yet the story of this discovery is 
not simple, for it required a great volume of tedious work 
and observation upon many patients. 


x PERNICIOUS ANEMIA 


We cannot say positively that eating liver is a cure for 
pernicious anemia, since continuous observation on pa- 
tients has not, as yet, exceeded three years. But it is a 
fact that those patients who have persisted in the diet 
have not only greatly improved but have remained com- 
paratively well. No such statement can be made regarding 
the efficacy of any other treatment ever tried. We justly 
regard this “liver treatment’? as the most startling dis- 
covery that has been made in connection with this disease, 
and as anextremely satisfactory means of treatment. 

As yet, this treatment has shed no definite light on the 
cause of the disease, but it has placed pernicious anemia 
in the same category as rickets in that it can now be con- 
trolled, although its nature is obscure. 


INTRODUCTION 


That the author has done me the great honor of invit- 
ing me to write an introduction to his monograph on 
PERNICIOUS ANAEMIA is due largely, if not entirely, 
to my interest in this disease. Since my three happy years 
(1902-1905) at the Johns Hopkins Hospital, as assistant 
resident physician in the medical service of the late Sir 
William Osler, I have tried to keep abreast of the litera- 
ture in this particular field. Then when in 1910 I moved 
to Iowa and directed a clinic of my own, I was delighted 
to find there a rich collection of anaemia cases available 
for study. With such a staff of well trained laboratory 
workers as Drs. L. Baumann, R. H. Gibson, R. L. Fen- 
lon, F. S. Stevens, G. H. Hansmann, and the co-operation 
of Miss Margaret Sawyer of the Home Economics De- 
partment of the State University and later of Dr. Ruth 
Wheeler, the professor of Dietetics of the Medical School, 
much intensive work was carried on over a period of 
years. Clinical, biochemical, and therapeutic problems 
were undertaken. While, with the possible exception of 
the clinical use of Whipple’s high iron diet for pernicious 
anaemia cases, nothing fundamental was contributed by 
us, we nevertheless were of necessity constantly in touch 
with the literature on this fascinating subject. As the 
reader will soon learn this was no light task, as both in 
Europe and in America a great many workers were striv- 
ing to determine the etiology of this disease, or failing in 
this to develop at least some more successful line of 
therapy than that in vogue at the beginning of the present 
century. From a more or less intimate knowledge of the 
enormous literature I think the author, Dr. B. S. Cornell, 
is to be sincerely congratulated on his clear, concise, and 
unprejudiced presentation of our knowledge, or possibly 
I should say our lack of knowledge, of the fundamental 


[xi ] 


xii PERNICIOUS ANEMIA 


phenomena underlying Pernicious Anaemia. This mono- 
graph will, I feel certain, prove of great assistance to the 
present and future students of haematology and will 
occupy a well-deserved place on the book shelves of every 
medical school as well as of many physicians’ libraries. 


C. P. Howarp, B.A., M.D. 
Professor of Medicine, McGill University 
Physician to the Montreal General Hospital 


AUTHOR’S PREFACE 


In a disease of unknown etiology every clinician ulti- 
mately develops his own peculiar view-point, expands it, 
arranges all the phenomena of the disease in some rela- 
tion to it, and may therefore find, in any treatise on the 
subject, other arrangements and other points of emphasis 
seemingly at variance with his own. Pernicious anemia 
lends itself well to such diversified conceptions on account 
of the broad symptomatology and wide tissue involvement 
which it presents. In the etiological field, theories have 
blossomed by the score through the decades since 1820, 
indicating the strong imaginative appeal which the disease 
has made to medical men. Few of these hypotheses are 
ridiculous, yet some enunciated most dogmatically are 
least convincing, and even those most supported by fact 
have proved inadequate. Experimentally, no blood picture 
of a convincing character has yet been produced, nor have 
the cord lesions, the glossitis, or the remissions been imi- 
tated. Diagnosis is the one well-cultivated field, yet differ- 
entiation from certain other anemias is at times ex- 
tremely difficult. If time has taught one inescapable lesson, 
it is that from 1820 to 1926 no cure existed, and yet 
writers, deceived by the occurrence of spontaneous remis- 
sions, have continued to fill the journals with descriptions 
of innumerable forms of treatment. These must be re- 
garded with great caution and deductions made gradu- 
ally over years of time, not months. 

In the literature of few diseases has there been so 
marked a tendency to mix fact with fiction. This is to be 
largely explained by the striking challenge to hypothesis 
which the disease characteristically makes. An average 
journal contribution contains a small amount of informa- 
tion and a large amount of speculation. Not infrequently 
the two become badly confused. This unpleasant state of 


[ xiii ] 


xiv PERNICIOUS ANEMIA 


the literature in general is increased by a tangle of nomen- 
clature inherited from the last century. A great many 
investigators, however, have had very clear motives, and 
their contributions are pleasant to read. 

The Surgeon-General’s Library in Washington con- 
tains about two thousand references to this subject. The 
fact that almost half of these have accumulated during 
the past decade, whereas the disease has been before the 
profession more than seven decades, indicates not only an 
increasing habit of publication, but a greater recent inter- 
est in pernicious anemia. It might be possible to build 
the entire story of our knowledge of the disease on the 
one hundred most important papers which have appeared. 
The omission of others, however, would rob one of an 
array of theoretical exposition—the psychology of the 
subject—which, in itself, affords considerable fascina- 
tion. 

Northern Europe, the British Isles, the United States, 
and Canada are at once the regions of highest incidence 
of the disease and of greatest investigation and publica- 
tion. The Atlantic Ocean has always divided pernicious 
anemia into two or three ill-defined schools of thought. 
On the continent, the characteristic attitude remains, as 
it has always been, one permitting a wide definition of 
the disease; with a tendency during the past twenty 
years to regard the idiopathic (or true) pernicious 
anemia as due to chronic intestinal intoxication. In Eng- 
land the disease is strictly Addisonian—limited to idio- 
pathic cases—and is usually regarded as due to sepsis of 
the digestive tract. In North America the term “perni- 
cious anemia’”’ is reserved for the idiopathic or Addison- 
ian complex, and the general etiological attitude is more 
confessedly one of rather complete agnosticism. 

Animal experimentation has contributed in a relatively 
minor capacity to our knowledge. The disease seems to 
be a specific possession of man, and the investigations of 


AUTHOR’S PREFACE XV 


greatest importance have been those conducted on 
patients with the disease. The most enlightening contri- 
butions have been those made possible by newly discov- 
ered methods of examination. Anilin blood stains, the 
hemocytometer, the stomach tube, the metabolimeter, ac- 
curate methods in the chemistry of the blood, the advance 
of dietary studies—these have all added valuable infor- 
mation. The newly discovered value of a diet rich in liver 
is unquestionably the most striking fact which has yet 
been presented. 

Among the comparatively few books which have been 
devoted specially to pernicious anemia may be mentioned 
those of Miller (1877), Eichhorst (1878), William 
Hunter (1901) (1909), and Evans (1926). Among the 
comprehensive monographs may be mentioned those of 
Cabot, Minot, French, Vogel, Moffit, Squier, and 
Schauman and Saltzman. To these works the author 
gratefully acknowledges his indebtedness. 

The present volume attempts to afford a critical review 
of the literature, to give a picture of the disease in the 
light of present knowledge, to increase the interest of the 
general practitioner in a subject which has received too 
little interest in the past, and, finally, to recommend earlier 
diagnosis and such form of prophylaxis as may be em- 
ployed. With these ideals in mind, this book has been 
prepared and is offered to the profession with the sincere 
hope that it may be found useful. 

Royal Victoria Hospital, BS. ce 


Montreal, Canada, 
May 24, 1927. 


5 


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CONTENTS 


PAGE 


FOR NON-MEDICAL READERS v 
INTRODUCTION xi 
AUTHOR’S PREFACE xiii 
CHAPTER I DEFINITION—CLASSIFICATION— 
DISTRIBUTION 3 
CHAPTER II HISTORICAL OUTLINE 16 
CHAPTER III ETIOLOGY 31 
CHAPTER IV GENERAL SYMPTOMATOLOGY 79 
CHAPTER V THE DIGESTIVE SYSTEM 88 
CHAPTER VI THE BLOOD SYSTEM 113 
CHAPTER VII METABOLIC OBSERVATIONS 183 
CHAPTER VIII THE NERVOUS SYSTEM 195 


CHAPTER IX CARDIOVASCULAR, RESPIRATORY, 
GENITO-URINARY, AND OTHER 


SYSTEMS 207 
CHAPTER X DIAGNOSIS AND PROGNOSIS 215 
CHAPTER XI PROPHYLAXIS AND TREATMENT 228 


AUTHOR-SUBJECT INDEX OF BIBLIOGRAPHY 
CONSIDERED 242 


INDEX 299 





PERNICIOUS ANEMIA 





CHAPTER I 


DEFINITION—CLASSIFICATION— 
DISTRIBUTION 


DEFINITION 


Pernicious anemia is a disease of unknown etiology, 
showing a characteristic triad of changes in the digestive, 
blood and nervous systems and progressing, usually by 
remissions, to a fatal termination. 


CLASSIFICATION 


The disease as a whole, considered from the stand- 
point of its common involvement of various systems, 
bears no very great resemblance to any other disease. 
Eventually it may be classified among the metabolic, or 
possibly the infectious, diseases. The anemia, which at- 
tends it so obtrusively as to have given it its name, re- 
quires classification. Any anemia is the result of one or 
more of the following factors—hemorrhage, blood de- 
struction, and depression of hemopoietic function. The 
anemia under consideration is believed to be due to a 
combination of the two latter causes, with an added fac- 
tor, namely, that the blood-forming function is not only 
depressed quantitatively but is also qualitatively per- 
verted. Otherwise expressed, blood corpuscles are being 
destroyed, they are being produced in insufficient num- 
bers, and those which are produced bear evidence of 
abnormal manufacture. The relative influence of blood 
destruction, on the one hand, and of hemopoietic depres- 
sion, on the other, in producing the anemia, is by no 
means clearly defined, although both phenomena defi- 
nitely occur. The term “hemolysis” should be restricted 
to indicate a physiological process by which a red blood 
corpuscle releases hemoglobin, and may be used in con- 
nection with many known in vitro phenomena. It is not 


[3] 


4 PERNICIOUS ANEMIA 


perfectly correct to speak of this anemia as “hemolytic,” 
as the loss of hemoglobin is not the striking feature. The 
striking feature is cellular phagocytosis, and this is the 
only known mechanism of blood destruction in this 
disease. Nevertheless, the term “hemolytic” is used fre- 
quently as synonymous with “blood-destructive”, and it 
has crept into the nomenclature to such an extent as to be 
often unavoidable. 

The bone-marrow shows enormous erythroregenera- 
tive activity in the form of an early embryonic type of 
blood formation. Similar pictures may be found in a few 
other instances, e.g., the chronic hemolytic anemia of 
pregnancy, some cases of fish tape-worm infection, some 
cases of cancer of the stomach, some cases of sprue, as 
well as certain other conditions to be mentioned presently. 
Waugh (637) in referring to these anemias, states: “The 
bone-marrow becomes brick red and often erythrogenesis 
is taken up by the spleen and liver . . . the color-index 
is high . . . such a condition may be termed therefore, 
hyperchromic. We find this type of anemia in certain 
cases of lues, sometimes associated with pregnancy, in 
the intoxication resulting from the fish tape-worm, also 
from the hook-worm, and especially in pernicious ane- 
mia.’’ He would therefore group these together as hyper- 
chromic, hemomyelotoxic anemias, and regard the anemia 
of pernicious anemia merely as the idiopathic member of 
the group. The position can be seen from Table I, show- 
ing Waugh’s classification of the anemias. 


TABLE 1 
Outline of classification of the anaemias (Waugh). 
A. Hemopathic (blood). 
1. Hemorrhagic (loss of blood). 
2. Hemotoxic (destruction of blood). 
B. Myelopathic (bone-marrow). 
1. Hemomyelotoxic (blood and bone-marrow). 
(a) Aplastic. 
(b) Erythroplastic (hypochromic). 


CLASSIFICATION—DISTRIBUTION 5 


(c) Erythrohyperplastic (hyperchromic). 

2. Myelotoxic (wasting away). 

3. Dyscrasic (dysharmonic, dysformative, dystrophic). 
This classification of the anemias and this characteriza- 
tion of pernicious anemia as an idiopathic member of 
the group of hyperchromic, hemomyelotoxic anemias, 
are as satsfactory as any offered. The very attempt to fit 
pernicious anemia into any group emphasizes its essen- 
tial dissimilarity, and it is felt that too great stress should 
not be placed upon classification. On the contrary, the 
disease should be studied first as a distinct phenomenon 
of nature, and comparisons left until later. 


THE NAME OF THE DISEASE 


The following names are among those which have 
been used, at various times, and by different writers, to 
designate the disease—idiopathic anemia, essential ane- 
mia, lethal anemia, pernicious anemia, primary progress- 
ive pernicious anemia, Biermer anemia, Biermer disease, 
Biermer-Erlich anemia, Addisonian anemia, Addison’s 
anemia, Addison-Hunterian anemia, idiopathic glossitic 
anemia. 

Any discussion of the relative merits of these names 
shows that objections can be raised to each one. In Ger- 
many and Switzerland, Biermer anemia is the choice. 
In England during the past ten years Addison’s anemia 
has been the common designation. In the United States 
and Canada, pernicious anemia has remained the sim- 
plest, the time honored, and perhaps the fairest, title. The 
term “primary” reflects a scholastic era in that it is the 
grammatical opposite of “secondary”, but modern intelli- 
gence cares to attach the adjective “uncaused” to but few 
phenomena. In retaining “pernicious anemia’, it is nec- 
essary to exclude all cases of anemia in which a cause 
can be noted and to use the term, therefore, in a much 
more restricted sense than that in which it was first pro- 


6 PERNICIOUS ANEMIA 


posed. So far from being discarded because of its depress- 
ing effect on the patient, it should be preserved because 
it impels the patient earlier to seek advice. Even when the 
etiology is finally elucidated, it is questionable whether 
even better knowledge will discard this familiar name. 


GEOGRAPHIC DISTRIBUTION 


It has been recognized for fifty years that the disease 
is commoner in Northern Europe, the British Isles, and 
North America than elsewhere. Evans (177) quotes 
Klotz to the effect that it is very uncommon in Brazil. 
Cheng (109) stated that he had never seen a case among 
the natives in China. It is apparent from the experience 
of Longcope at Baltimore, and of others, that the disease 
seldom if ever occurs in a full-blooded negro. Jews are 
said to be uncommonly affected. Specific information is 
lacking from many quarters of the globe, but the writer 
sent out letters in November 1925 to many countries 
seeking mortality statistics. In Germany the hospitals 
have the only records. In Australia the Bertillon classi- 
fication groups pernicious anemia with certain other 
forms of anemia. The same grouping is used in Sweden, 
but Gram kindly produced the required information from 
special sources. In England the Statistical Reviews of the 
Registrar General contain figures for pernicious anemia 
(H. M. Stationery Office, Adastral House, Kingsway, 
London, W. C., 2, at 15/- each). South Africa collects no 
morbidity statistics; however, the number of European 
deaths from it, registered in the Union during the years 
1914-1924 averaged 43 per year, although the European 
population is not stated. In Newfoundland for 1924 the 
deaths from pernicious anemia combined with other 
anemias and leukemias were 6 per 100,000 of population. 

The Surgeon General of the United States reported 
from the registration areas for 1921 and 1922 as follows: 


CLASSIFICATION—DISTRIBUTION vs 


TABLE 2 
Deaths from pernicious anemia in the United States 


1921 1922 
itemanenmetndeatiosy 2 corso Ae ade 4377 4979 
Death rate per 100,000 of population...................... 49 aes 


Additional details may be found in the annual volumes 
of mortality statistics issued by the Bureau of Census. 
Since the average duration of the disease, up until now, 
has averaged 2.2 years, it is safe to state that in the 
United States at any time there are 10,000 cases, at the 
lowest estimate. 

In Denmark, the deaths for 4 years, outside Copen- 
hagen, are shown by the statistics in Table 3. 


TABLE 3 
Deaths in Denmark outside Copenhagen 
No. of deaths National Deaths per 
from pernicious population 100,000 
anemia outside Copen. population 
1OZO May nei yh 63 2,524,650 225 
GAM ee Bee ce La 68 2,721,500 2.5 
O22 Mie eee ee at 85 2,752,700 Sul 
SDV es coe aie Se 83 2,767,500 3.0 
LOZ Aver ee 123 2,788,150 44 


Separated statistics for the urban and rural sections 
outside Copenhagen are shown in Table 4. 


TABLE 4 
Deaths in Urban and Rural Denmark outside Copenhagen 
No. of deaths Total urban Deaths per 


from pernicious population 100,000 
anemia outside Copen. population 
1 Ge? Se Ps 765,700 23 
Soe ee 30 825,250 3.6 
1/27 ao See ZA 835,900 Bd. 
613 Se aes 31 840,100 3:7 
IS 74 ee a ee 46 839,200 Df 


8 PERNICIOUS ANEMIA 


Deaths per 
100,000 
population 

2a 

2.0 

3.0 

Zed 

3.8 


Deaths per 
100,000 
population 
25 
Sy 
25 
0.9 
£5 
3.6 
4.0 
48 
6.0 


No. of deaths Total 
from pernicious rural 
anemia population 
1920 eee 42 1,758,950 
11277 BE Sl 38 1,896,250 
1977 Nate eee 62 1,916,800 
OZS sae sees 52 1,927,400 
NODA tl Beene 77 1,948,950 
Figures for the City of Copenhagen are found in 
Table 5. 
TABLE 5 
Deaths in Copenhagen 
Deaths from Population 
pernicious of Copen- 
anemia hagen 

BO OD a2 et ses Ae eee 10 416,540 [Est.] 
POG acess Ba ee 13 426,540 [ Act. ] 
TSO 7 Soe Reeth ee 11 434,540 [Est.] 
ROOS 2 eye ees 4 442,540 [Est.] 
NOOO eee Eee ai 450,540 [ Est. ] 
(SS ae ee 18 491,161 [Est.] 
HIS (ICR Peete state 20 506,390 [ Act. ] 
SR ee ae 28 573,295 [Act.] 
1O24 a eee 5) 581,295 [Est.] 


Examination of these tables indicates a slight increase 
in reported cases especially in the period 1921-1924, and 
particularly in the urban population. Such increase is 


really small and may justly be attributed to 


better diag- 


nostic facilities in the cities. The investigation recently 
undertaken in Germany by Schilling at Magnus-Levy’s 
suggestion showed, however, a 3- to 4-fold increase of the 


disease at German clinics (521). Gram 
Sweden the following figures (Table 6). 


TABLE 6 
Deaths in Sweden 
Deaths from 


pernicious Population 

anemia of Sweden 
DS ea Ds BA ee 82 2.5M 
LONG ee Re calle 2d. 87 2.5M 


reports for 


Deaths per 
100,000 
population 
BE 
3.4 


CLASSIFICATION—DISTRIBUTION 9 





DO ee eens 8 aS ‘ 87 2.5M 3.4 
MOS eee ete dh 76 2.5M 3.0 
CIN ps hs Meee Nee Ame 86 2.5M 3.4 
Oe Soe oe oe ts 88 2.5M a5 
POS nee is 95 2.5M 3.8 
IND |G ee ee oe cme 68 2.9M Zh 
SZ ers eens 79 2.5M 3.1 
LING PAL Salle DA Re ene 96 2.9M 3.8 


Nova Scotia in 1923 showed an incidence of 4.8 deaths 
per 100,000 of population. Saskatchewan showed a com- 
bined rate for anemias and chlorosis of 9.2 per 100,000, 
for 1923. New Brunswick in 1924 showed a death rate 
from pernicious anemia of 9.0 per 100,000 of population . 
but somewhat lower rates for the preceding four years. 
Quebec Province showed the following rates: 


Year No. of Deaths Rate per 100,000 population 
1921 71 3.0 
1922 69 2.8 
1923 66 2.8 
1924 73 25 


British Columbia showed the following figures: 


Year No. of Deaths Rate per 100,000 population 
1921 34 6.0 
1922 41 8.0 
1923 4] 8.0 
1924 50 10.0 


Alberta in 1923 showed 26 deaths in a population of 
588,000 or a rate of 4.3 per 100,000 among the white 
population, exclusive of Indians. 

Ontario shows a very high incidence of the disease, as 
the following figures will indicate: 


Meat Population Deaths Rate per 100,000 population 


1922 2,981,182 437 14.6 
1923 3,028,907 454 15.0 
1924 3,062,150 433 14.1 


So high a figure has not been noted from any other regis- 
tration area from which statistics have been received. 


10 PERNICIOUS ANEMIA 


As the deaths from all causes total 33,000 to 35,000, 
those from pernicious anemia form from 1.28 to 1.31 per 
cent of the total deaths! The reasons for this exception- 
ally high incidence in Ontario are not apparent, but that 
it is a reality has been impressed upon the writer during 
several tours of Ontario. Whereas in most regions of the 
world a general practitioner may see from three to five 
cases during twenty years’ practice, nearly all physicians 
in Ontario will treat a case every two or three years, 
and it is not uncommon to find a physician with two or 
three cases at a time, and two physicians with small- 
town practices have at present four and five cases on 
hand, respectively. 

Even without statistical studies it has been recognized 
for some time that Michigan, Ontario, New Brunswick, 
and the Eastern Townships of Quebec present high rates 
of incidence. While no detailed study of the incidence in 
Ontario by counties has been made, an apparent accentu- 
ation seems to occur annually in the counties bordering 
the first reaches of the St. Lawrence River, especially 
Leeds and Grenville, and the centre of the Western 
Peninsula from Woodstock to London and thereabouts. 

Ontario shows as well a high incidence of simple goitre, 
and in recently studying 85 cases of pernicious anemia at 
their homes in Ontario, the writer noted the occurrence 
of simple goitre in 3 of these patients. Whether further 
study might establish a relationship between pernicious 
anemia distribution and geological structure is uncer- 
tain, but it is of interest to note that Montgomery (452) 
in investigating the distribution of the disease in Western 
Canada found that areas of highest incidence were those 
in which the drinking water was the most highly saline. 
Moreover, he observed that in these areas the individuals 
acquiring the disease were the Anglo-Saxon, lifelong 
inhabitants and seldom, if ever, the more recently settled 
Scandinavian immigrants. A similar study ought to be 


CLASSIFICATION—DISTRIBUTION Is 


made in Ontario. Furthermore, the diets of Ontario 
should be investigated, as there is some reason to believe 
that the rural inhabitants, particularly in winter, tend to 
consume an ill-balanced diet and one deficient in the 
“protective” food-stuffs. 


SEX INCIDENCE 

Levine and Ladd (369) found the proportion of males 
to females as 2 and 3 in 150 consecutive cases. It is gen- 
erally considered that the incidence is slightly higher in 
men than in women. Eason (158) found this true only 
after the age of 50, before which the conditions were 
reversed. Sex statistics are very variable. From the mor- 
bidity statistics from various sources the following infor- 
mation is assembled. (Table 7). 


TABLE 7 


Sex incidence figures from various sources 


Source Total Male Female 
leva Scotia wee ee ee 34 17, 17 
PANT betters eau Pie wie 26 14 12 
British Columbia .............- 166 101 65 
New Brunswick .............. 36 18 18 
Copenhagen’ 00006 os 146 58 88 
Sombie Atirical eas eee 474 226 248 
Sweat eee ine 844 385 459 

PRG EAIS 2220 ete 1,726 819 907 


In most computations differences of much significance 
seldom occur. 
AGE INCIDENCE 

Pernicious anemia is a disease of senescence, showing 
the highest incidence between 45 and 55. It is not uncom- 
mon to meet cases in the late twenties. Davison told the 
writer that in ten years experience at the Harriet Lane 
Home, where only children under 15 are admittd, no case 
had been encountered. 

Cases reported among children would require very 
careful confirmation. Of the 29 cases in children reported 


We PERNICIOUS ANEMIA 


by Mensi it is practically certain that the majority if not 
all were either severe aplastic anemias or splenic syn- 
dromes, due to causes apparent or obscure. The remark- 
ably interesting case of severe anemia in a boy of 8 years, 
reported by Morse and Wolbach, would, from their de- 
scription, probably have received a diagnosis of perni- 
cious anemia without question, although they do not men- 
tion the state of the gastric secretion. Barr (26) records 
the case of a boy of 16, dying of severe anemia, in which 
the insidious onset, lemon-yellow pallor, blood picture, and 
state of the gastric secretion (achlorhydria) were all con- 
sistent with a diagnosis of pernicious anemia, although 
neither cord symptoms nor glossitis were noted. Naegeli 
admits only 3 real cases of pernicious anemia in children. 
These have been fully described by Hotz (277). The out- 
standing one of the three is the now famous case of Mar- 
grith Ritter, aged 4 years, who died with every sign 
required to confirm the diagnosis of cryptogenic perni- 
cious anemia. The second case, that of Anna Koch, aged 
11 years, began with pallor, weakness, anorexia, diar- 
rhoea, abdominal pain, occasional fever, and a gradual in- 
tensification of the anemia. Following iron and blood in- 
jections, a good remission occurred, the tongue which had 
been gelatinous-looking became normal, and the reflexes 
and blood picture returned to normal. After some months 
the anemia recurred, treatment proved futile, and she died 
of broncho-pneumonia. The third case, that of M.W., a 
9 1-2 year old girl, was, on admission, a typical example 
of Herter’s intestinal infantalism, with pyelitis and simple 
anemia. In the course of a few months the emaciation and 
weakness grew worse, periods of fever occurred, and a 
pernicious-like anemia developed. After some further 
months a sudden improvement was noted, the signs of 
Herter’s disease disappeared as well as the pyelitis, and 
the anemia became of simple type. 


CLASSIFICATION—DISTRIBUTION 13 


Vischer (629) has intelligently considered these perni- 
cious-like anemias of children. He shows that in the se- 
vere anemias of children a greater uncertainty exists than 
in adults, because the reaction of the youthful erythro- 
myeloid tissues deviates from the reaction of those of the 
adult. He agrees with Morawitz that the course of many 
anemias in children is characterized by a very high capa- 
city for regeneration, abundance of embryonic types of 
cells in the blood stream, a speedy development of extra- 
medullary foci of blood formation, and a generally fa- 
vourable course, with the result that a complete cure 
may occur in a condition which would be diagnosed as 
pernicious anemia in an adult. Evans and Happ (178) 
have noted the unjustifiable tendency to diagnose infan- 
tile pseudoleukemic anemia on the basis of splenic en- 
largement which means, in children, often nothing more 
than a characteristic infantile response to anemias of va- 
rious types. Evans (177) states that among the first 
36,000 non-surgical patients under fourteen years of age 
treated in the Harriet Lane Home, no case of pernicious 
anemia was encountered, and that Howland developed a 
decided skepticism toward the possibility of the diagnosis 
in children, believing that some so diagnosed were pur- 
puras or lymphoid leukemias. Bass (30) and his associ- 
ates found no increased urobilin excretion in a series of 
infantile anemias, thus emphasizing the non-hemolytic 
and moderately aplastic tendency which usually obtains. 
Tecon’s (609) case in a child of six was frankly aplastic. 
Agnew (6) viewed his case as definitely aplastic with no 
suggestion of pernicious anemia. The purpuric tendency 
noted by Agnew is common in these severe aplastic ane- 
mias of children and causes them at times to merge with 
the purpuras (see McElroy 416). Sufficient has been 
written to make it appear questionable whether pernicious 
anemia ever occurs in children. 


14 PERNICIOUS ANEMIA 


The opposite extreme of age is likewise not entirely 
free of difficulty, inasmuch as a superficial resemblance 
to pernicious anemia is constituted at times by old age it- 
self. Gilford (226) in his somewhat dogmatic claim for 
premature senescence of the erythropoietic tissues as the 
cause of Addison’s anemia, states that he has seen the 
blood of the aged simulate the picture of this disease, but 
omits giving detailed examples. Evans sums up this diffi- 
culty in his book and shows how superficial such resem- 
blances really are: “The cachexia of old age may simulate 
pernicious anemia. Here the complexion is often sallow, 
one frequently encounters an achylia, and there may be 
anemia. The sallowness of the elderly is not, however, the 
same as that seen in pernicious anemia, although it may 
resemble it closely. In the former it is usually an absence 
of color, or a grayish tint, differing from the peculiar 
yellow color of the latter. Furthermore, a discoloration of 
the skin in the elderly, which may lead one to suspect per- 
nicious anemia is usually only seen in them when there is 
emaciation and the resultant wrinkles. In pernicious 
anemia emaciation is most uncommon, and the com- 
plexion is usually smooth. The achylia gastrica should not 
confuse, as it is a common finding in advanced age. The 
anemia in these patients is dependent on a general lower- 
ing of the hemopoietic, together with other functional 
activities, and is usually readily differentiated from that 
of pernicious anemia. Poikilocytosis, anisocytosis and 
polychromasia may be present, but are usually of mini- 
mal grade even when the anemia is severe.”” He empha- 
sizes, as well, a normal ratio of polymorphonuclear leuko- 
cytes even when, in old age, a leukopenia is present. Ward 
(634) has shown, however, that the disease may occur in 
very old people. Including Templeton’s (611) cases, seven 
have been reported in persons at 70 or older. 

Hunter has always claimed a high seasonal incidence in 
the summer months. An isolated confirmation of this ob- 


CLASSIFICATION—DISTRIBUTION 5 


servation comes from Bartlett (29) who noted in a cer- 
tain section of Pennsylvania, not only a great deal of per- 
nicious anemia, characterized by initial glossitis and oral 
tenderness, but a quite definite incidence in the spring. 
Owing to the coincidence of the maple-sugar industry at 
this period of the year, a superstition had gained ground, 
in this neighborhood, that the sore tongue and the anemia 
were due to eating maple sugar. In Ontario, in several 
districts a similar suspicion has been directed towards 
rhubark, possibly for the same reason. Further observa- 
tions on seasonal incidence would prove of considerable 
interest. 


CHAPTER II 
HISTORICAL OUTLINE 


Combe (128) described the first recorded case in May, 
1822. Previous to that date, the disease was confused 
with other severe anemias such as those of ankylostomia- 
sis, sepsis, and chlorosis. Since modern mortality statistics 
do not indicate any more increase than might be due to 
improved diagnostic knowledge, it cannot be assumed 
that it is a disease of modern civilization. The absence 
of reports before Combe’s may well be due to confusion 
and the lesser glibness of our medical predecessors. 

“T was much struck by his peculiar appearance,” 
Combe wrote. “His lips, face and the whole surface were 
of a deadly pale colour; the whites of the eyes bluish; his 
motions and speech languid; he complained much of weak- 
ness; his respirations, free when at rest, became hurried 
on the slightest exertion; pulse 80 and feeble; inner parts 
of the lips and fauces nearly as colourless as the surface; 
bowels very irregular, generally lax, his stools very dark 
and foetid; urine reported to be copious and very pale; 
appetite unimpaired, of late his stomach had rejected 
almost every kind of food; constant thirst; he had no 
pain referable to any part and a minute examination 
could not detect structural derangement of any organ. 

“Post mortem. The subcutaneous fat was scanty, of a 
pale yellow colour and semi-fluid. Not a drop of blood 
escaped on dividing the scalp. The heart when cut into 
was of a pale colour, and did not tinge linen when rubbed 
upon it; it appeared like flesh macerated many days in 
water. The right ventricle contained a pale coagulum. 
The left side was wholly empty. There was a considerable 
moisture bedewing the viscera of the abdomen. The liver 
was of its proper size and structure but of a light brown 
colour; the spleen was the only organ which retained its 


[ 16] 


HISTORICAL OUTLINE 17 


normal red colour; it was very soft, and its contents on 
pressure being applied, turned out like a sac.” 

Combe could find nothing in the history, the environ- 
ment, or habits of this patient to explain the condition. 
He was confessedly non-plussed and fell back on the 
obtrusive gastro-intestinal symptomatology for an expla- 
nation. “It is probably,” he wrote, “owing to some dis- 
order of the digestive and assimilative organs that its 
characteristic symptoms have their origin.”? Anemia in 
his day was no more successful than at present in its 
claim to the rank of an entity, but was generally regarded 
as but a symptom of some stated, bodily process. Combe, 
however, could not disabuse his mind of the impression 
that, in the spectacle of this case, he had witnessed the 
working out of a law, obscure indeed, but nevertheless 
self-contained and inevitable. He states, “. . . if any 
train of symptoms may be allowed to constitute anemia 
a generic disease the following may be considered an 
example of it in its most idiopathic form.” 

Channing (106) as early as 1842 described severe 
anemia occurring in puerperal cases. His cases depended 
on the presence of sepsis of the endometrium and are not 
to be confused with the chronic hemolytic anemia of 
pregnancy which resembles pernicious anemia so closely. 

Elliotson’s (171) Practice of Medicine, 1846, refers 
to certain cases of grave anemia, which from his descrip- 
tion were probably Addisonian. He wrote of the great 
debility, corpse-like appearance, wax-like skin, blue scler- 
otics, colorless mouth and tongue, the feeble pulse readily 
excited, the bad appetite, constant thirst, sweating and 
terminal edema of the legs. He mentioned an “aggravated 
species” with dark foetid stools, nausea, and constant 
vomiting, which showed at autopsy “internal softness 
and paleness’, lack of blood, and excess fluid in the serous 
membranes. He referred to Combe’s case and noted that 
no etiology had been discovered. He praised iron in treat- 


18 PERNICIOUS ANEMIA 


ment but admitted that “relapses were very usual.” He 
then offered a theory, based on an idea of compensatory 
congestion and anemia occurring simultaneously in dif- 
ferent parts of the body, due to the action of emotion or 
gravity. Finally he quoted Andral,—“organs look anae- 
mial less from lack of blood than from lack of colouring 
matter”—the disease being thus construed as a degener- 
ation toward a condition normal in white-blooded 
animals. 

Before and during this period Thomas Addison, phy- 
sician to Guy’s Hospital, London, had become keenly 
interested in a group of cases presenting pallor and 
asthenia. It later transpired, through distinctions drawn 
by Addison himself, that this group contained really two 
diseases; first, disease of the suprarenal glands or Addi- 
son’s disease; second, the peculiar disease which forms 
the subject of this book. Since Addison’s time, Guy’s 
Hospital has always maintained a special interest in this 
anemia. Addison in 1849 under the tide of Anaemia, 
Disease of the Suprarenal Capsule, described the ane- 
mia as ‘a remarkable form of anaemia which though 
incidentally noticed by various writers, had not attracted 
by any means the attention it really deserved. It was a 
state of anaemia incidental to male adults and had been 
with him for years a subject of earnest enquiry. .. .” 
At this time he had not distinguished it sufficiently from 
the other disease. It was in 1855, in his introduction to 
his work, On the Constitutional and Local Effects of 
Disease of the Suprarenal Capsules, that he described it, 
for the first time in history, as a generic disease, under 
the name, “Idiopathic Anaemia” (5). 

“As a preface to my subject, it may not be altogether 
without interest or unprofitable to give a brief narrative 
of the circumstances and observations by which I have 
been led to my present convictions. 


EPS TORICAL OUTLINE 19 


“For a long period I had from time to time met with a 
very remarkable form of general anaemia occurring with- 
out any discoverable cause whatever—cases in which 
there had been no previous loss of blood, no exhausting 
diarrhoea, no chlorosis, no purpura, no renal, splenic, 
miasmatic, glandular, strumous or malignant disease. 
Accordingly, in speaking of this form in clinical lectures, I 
perhaps with little propriety, applied to it the term ‘idio- 
pathic,’ to distinguish it from cases in which there existed 
more or less evidence of some of the usual causes, or con- 
comitants of, the anaemic state. 

“The disease presented in every instance the same gen- 
eral character, pursued a similar course, and, with 
scarcely a single exception, was followed after a variable 
period by the same result. 

“Tt occurs in both sexes, generally, but not exclusively, 
beyond the middle period of life; and so far as I know at 
present, chiefly in persons of a somewhat large and bulky 
frame, and with a strikingly marked tendency to the 
formation of fat. 

“Tt makes its approach in so slow and insidious a man- 
ner that the patient can hardly fix a date to his earliest 
feeling of that langour which is shortly to become so 
extreme. 

“The countenance gets pale, the whites of the eyes 
become pearly, the general frame flabby rather than 
wasted; the pulse perhaps large, but remarkably soft and 
compressible, and occasionally with a slight jerk, especi- 
ally under the slightest excitement. There is an increasing 
indisposition to exertion, with an uncomfortable feeling 
of faintness or breathlessness on attempting it; the heart 
is readily made to palpitate ; the whole surface of the body 
presents a blanched, smooth and waxy appearance; the 
lips, gums and tongue seem bloodless; the flabbiness of 
the solids increases; the appetite fails; extreme langour 
and faintness supervene, breathlessness and palpitation 


20 PERNICIOUS ANEMIA 


being produced by the most trifling exertion or emotion; 
some slight oedema is probably perceived about the 
ankles. The debility becomes extreme; the patient can no 
longer rise from his bed, the mind occasionally wanders; 
he falls into a prostrate and half torpid state, and at 
length expires. Nevertheless, to the very last, and after a 
sickness of perhaps several months’ duration, the bulki- 
ness of the general frame and the obesity often present 
a most striking contrast to the failure and exhaustion 
observable in every other respect. 

“With perhaps a single exception, the disease in my 
own experience, resisted all remedial efforts, and sooner 
or later terminated fatally. 

“On examining the bodies of such patients after death 
I have failed to discover any organic lesion that could 
proper or reasonably be assigned as an adequate cause 
of such serious consequences; nevertheless from the dis- 
ease having uniformly occurred in fat people, I was nat- 
urally led to entertain a suspicion that some form of fatty 
degeneration might have a share at least in its produc- 
tion; and I may observe that in the last case examined, 
the heart had undergone such a change, and that a por- 
tion of the semilunar ganglion and solar plexus, on being 
subjected to microscopic examination was pronounced 
by Mr. Tuckett to have passed into a corresponding 
condition. 

“Whether any or all of these morbid changes are essen- 
tially concerned—as I believe they are—in giving rise to 
this very remarkable disease, future observation will 
probably decide. 

“The cases having occurred prior to the publication of 
Dr. Bennett’s interesting essay on Jeucocythemuia, it was 
not determined by microscopic examination whether 
there did or did not exist an excess of white corpuscles 
in the blood of such patients.” 


HISTORICAL OUTLINE 21 


This brief and famous description placed idiopathic 
anemia on a fairly firm basis as a clinical entity and dis- 
tinctive disease. Even before Addison’s work, Barclay 
(22) in 1851 described a case under the title, Death 
from Anaemia,—an important document because it con- 
tains the first mention in the literature of the glossitis 
which later, through the emphasis of Hunter, became an 
important diagnostic symptom. Many case reports fol- 
lowed between 1857 and 1871, notably by Wilks (655), 
who taught the disease to students, Cazenave (105), 
Bristowe (71), Habershon (244), Barclay and Dickin- 
son, and King (335). Palmer Howard in Montreal and 
Trousseau in Paris taught the disease in the ’sixties. 
Austin Flint, 1860, and Fenwick, 1865, suggested the 
possible dependence of some cases on degenerative 
changes in the gastric mucosa. Gairdner in his Clinical 
Medicine, 1862, recorded a case which he described as 
follows: “A mysterious form of anaemia . . . a remark- 
able case of pure anaemia, fatal, without any explanatory 
organic complication. The blood presents an extreme 
deficiency of red, and certainly no increase of white, cor- 
puscles. After death which occurred from pure exhaus- 
tion, every organ was carefully examined, and the only 
morbid appearance presented were in the heart, liver and 
kidneys, which were all more or less occupied by fatty 
granular deposit. I have only to say in regard to this most 
mysterious form of disease that it has no real relation to 
the chlorosis of young women. In fact the only two cases 
which I have seen exactly resembling this one, occurred 
in men and at middle age. The general appearance is much 
more that of malignant disease than of any other condi- 
tion with which I am familiar.” 

In Germany, Lebert (364) described it in 1858 under 
the name essential anemia. From his narrative, especially 
with regard to the mortality, it is evident that either his 
follow-up records were imperfect or that he grouped with 


22 PERNICIOUS ANEMIA 


the others some cases not of the idiopathic variety. “In a 
series of cases I have observed the whole picture of 
anemia without any organic cause, and without finding 
anything post mortem to explain it; and I have therefore 
termed these cases, essential anemia. This idiopathic ane- 
mia seldom ends fatally; when it does, one finds no organ 
essentially diseased. In rare cases idiopathic anemia may 
end fatally, even without being complicated by any loss 
of blood or any organic disease . . . we should not for- 
get therefore that anemia can, of itself, though seldom, 
lead to death.” 

Perroud (496), earliest of the French school to observe 
the disease, emphasized the fatty transformation of the 
liver as the etiological factor, and the anemia, cachexia, 
and edema as results. 

Curiously little impression, however, seems to have 
been made on English and Scotch writers by Addison’s 
important communication. Striking evidence of this is 
the fact that Bennett in his Practice, 1867, totally ignores 
the subject, the more striking since he was sufficiently 
interested in blood to have been the discoverer of leukemia. 
Tanner, 1869, likewise makes no mention of idiopathic | 
anemia. But Guy’s Hospital Reports from 1864 to 1878 
contain 23 cases, collected by Taylor. 

English medical attention was really roused, not by 
Addison’s description but by an editorial in the Medical 
Times and Gazette, in the November, 1874, issue on page 
581, entitled ‘“Pernicious Anaemia: a new Disease,” 
which reviewed the work of Biermer and of Immermann 
and stated, ‘““We are not aware that any case has as 
yet been reported in Great Britain; but no doubt there 
will soon be many observers on the look-out for it.” Addi- 
son’s death in 1860 saved him from a realization of the 
inglorious lot of the prophet in his own country. 

Biermer of Zurich published several papers between 
1867 and 1872 on this disease but improved on Addison’s 


EUSTORICAL OUTLINE Z3 


description merely in mentioning the tendency to small 
hemorrhages. His conception was more inclusive than 
Addison’s, for his designation, pernicious anemia, took 
in several types of anemia, such as bothriocephalus, car- 
cinoma, malaria, as well as Addison’s idiopathic. To all 
of these Biermer applied the term progressive pernicious 
anemia, and to the latter, as a distinguishing appellation, 
the prefix “primary”. His work was original and impor- 
tant. Addison, however, was later accorded, even by Con- 
tinental writers, the priority he deserved. Although 
Biermer’s publications served the function of stimulating 
general medical interest in a neglected subject, it is to be 
regretted that not only his broad definition but his con- 
fusing nomenclature have remained, though not unas- 
sailed, somewhat to the present. 

The account of Biermer (60) may best be presented 
by repeating Hunter’s résumé: 

“Professor Biermer gave an address on a form of pro- 
gressive pernicious anaemia, often observed by him, 
which seemed to be generally associated with fatty degen- 
eration in the circulatory apparatus, and, in consequence, 
with capillary haemorrhages in the skin, retina, brain, 
meninges, and other serous membranes. He had observed 
the peculiarities of this form for the last five years, and 
had already, 1868, made a preliminary communication 
upon it. Since then the number of his cases had increased 
to fifteen, so that it could be said that the disease, in the 
Canton of Zurich, at least, was not uncommon. It was 
found amongst poor people; especially in women about 
thirty years of age, among whom, in addition to poverty, 
puerperal conditions appeared to be favouring causes. It 
occurred, however, also among old and young of either 
sex. The youngest patient was 15, the oldest 52: insuffi- 
cient and unsuitable feeding, unhealthy surroundings, dis- 
charges—especially persistent diarrhoea—sometimes also 
haemorrhages, usually preceded the disease and caused it. 


24 PERNICIOUS ANEMIA 


The most common cause, according to his observations, 
was chronic diarrhoea with and without gastric distur- 
bances. Chlorosis appeared to be rarely a cause; it was 
but rarely also that the disease originated spontaneously, 
without a cause. Neither with splenic disease nor with 
malaria had the disease any connection. The only organic 
lesions which so far had been found in some cases, and 
which might be blamed for the disease, were follicular 
ulcers of the colon. 

“The symptoms were as follows: (1) Appearance of 
anaemia and hydraemia. Great pallor, poor nutrition, but 
no disappearance of subcutaneous fat as in cancer or 
phthisis; often a yellow-white complexion without jaun- 
dice. In advanced cases slight oedema of the face, feet, 
and hands; also some ascites. (2) The usual nervous 
symptoms of anaemia—weakness, giddiness, palpitation, 
etc. (3) Digestive disturbances consequent on the anaemia 
—anorexia, weak digestion, sometimes gastric discom- 
fort, very often periodic diarrhoea. (4) Circulatory dis- 
turbances—bruits in the heart and great vessels, the 
former so marked as often to raise the question whether 
valvular disease was present. The bruits were systolic; 
usually over the base rather than over the ventricle, where 
they were of a more blowing character. The murmurs 
were not always to be heard at first, but they always 
appeared later and became stronger. In the arteries of 
the neck bruits were also to be heard, occasionally also 
over the jugular vein. If the heart’s action were excited, 
the heart impulse diffused, and the cardiac dullness in- 
creased (as was often the case). The picture presented 
was very like that of cardiac disease, and might, especi- 
ally as fever was often present, be mistaken for endocar- 
ditis. Post mortem, however, nothing of the kind was 
discoverable, but simply partial fatty degeneration of the 
heart muscle. The heart’s action was usually quickened, 
the impulse diffuse and undulating, never strong. (5) 


HISTORICAL OUTLINE 25 


Fever was unessential, but was met with from time to 
time in nearly all cases; sometimes very slight, at other 
times more marked; without special type, and only for 
short periods. In one case it was for a time like that of 
typhoid, and it was for that condition that the patient 
was sent to the hospital. Usually it was slight and appar- 
ently causeless; hence in the clinic it was often for the 
sake of brevity termed anemia fever. He thought the 
fever was of a ‘humoral character’ but considered it also 
possible that the small haemorrhages in the body, as also 
the gastric disturbances, might be causes of it. Definite 
local causes of the fever were not to be found. (6) Of 
interest also were the retinal haemorrhages, which were 
generally present even in cases in which there were no 
subjective symptoms of visual disturbance. If absent in 
the first instance they usually appeared later. In one case 
they were so severe as to cause sudden loss of sight in the 
left eye. They were to be found post mortem, and formed 
very striking pictures. (7) Subcutaneous haemorrhages 
and petechiae were not so common. Haematuria and epis- 
taxis were only once observed, albuminuria quite excep- 
tionally. (8) Capillary haemorrhages in the brain, the 
subdural arachnoid, and the pia mater, were, on the 
contrary, common, sometimes without any characteristic 
symptoms during life. One patient died of a large capil- 
lary haemorrhage in the brain. Another was seized sud- 
denly with pain in the right arm and leg, impaired speech, 
right hemiplegia (including facial paralysis), the whole 
symptoms passing off in half an hour. Delirium was often 
present in the later stages. The course of the disease was 
in all cases one of gradual increase of anaemia and 
hydraemia, appearance and increase of heart symptoms, 
accidental capillary haemorrhages, serous effusions, occa- 
sional fever, consequent anorexia, and often diarrhoea. 
Pneumonia and erysipelas were rarer complications. 
Death occurred in all cases, with the exception of one, 


26 PERNICIOUS ANEMIA 


which left the hospital improved. Post mortem—lIn addi- 
tion to the anaemia there was generally found fatty 
degeneration of the musculi papillares of the heart, and 
of the small vessels, the former explaining the heart mur- 
murs and the latter the capillary haemorrhages. The 
papillary muscles appeared yellowish and mottled, the 
muscle of ventricular wall and septum was often similarly 
affected. It was exceptional, however, for the fatty degen- 
eration of the heart muscle to be excessive. In the large 
arteries there was nothing abnormal, or, at most, slight 
fatty degeneration of the intima; this latter was more 
common in the smaller arteries, e.g., of the kidneys; still 
more common in the capillaries, especially of the brain. 
In three cases small flat extravasations were found in the 
subdural arachnoid, without however, any sign of pachy- 
meningitis; they were therefore probably purely haem- 
orrhagic in origin and connected with the fatty changes 
in the capillaries. The capillary haemorrhages in the 
brain, retina, epicardium, and pericardium were to be 
referred to nutritive disturbances in the capillary walls. 
Both these and the fatty changes in the heart muscle were 
caused by the altered condition of the blood, and were 
analogous to the fatty changes caused in tissues by cutting 
off their blood supply. Liver, spleen, kidneys showed noth- 
ing special.” 

As before stated, Biermer’s work excited rhuch interest 
in England where Addison’s description had not made a 
very wide impression. On the continent it created so deep 
an interest that the disease is still known as Biermer 
anemia and most of his teaching receives current accep- 
tance. It will be evident that Biermer included in this 
group anemias of which the cause was known and there- 
fore not of the idiopathic variety specified by Addison. 
For this reason his description cannot be regarded as 
being so faithful as that of his English contemporary. 
Pye-Smith (506), a pupil of Addison, in an article in 


EISTORICAL OUTEINE 27 


Virchow’s Archiv in 1875 drew the attention of Ger- 
many to his master’s work. Later, in 1883, he (507) 
published a conclusive vindication of the identity of the 
disease and deprecated the tendency to merge it with other 
anemias in Biermer’s group of progressive pernicious 
anemia. 

The first monograph on the disease was that of Miiller 
(459) in 1877. Among Americans and Canadians at this 
period W. Pepper (493), Osler and Gardner (480), and 
Kinnicutt (337) were the chief writers on this subject. 
In Germany, Quincke (510), Eichhorst (165), Cohn- 
heim (123), Eisenlohr (167), Rosenstein (537), and 
Ehrlich (161-164) led opinion. In England, Bramwell 
(63) introduced arsenic in treatment and MacKenzie 
(390) stressed neurosis as an etiological factor. In 
America, Starr (589) as well as Cary (104) described 
successful blood transfusion in treatment. 

In 1886 Hunter (289) described intraperitoneal trans- 
fusion and in 1888 published an important paper on the 
pathology (292). Probably no person has spent more of 
his life in the study of pernicious anemia than Hunter. 
He has worked since 1885, publishing at frequent inter- 
vals, and his name will always be closely associated with 
the disease. Clinically and pathologically he is to be 
credited with greatly increasing our knowledge. Briefly, 
he had been ‘the strongest exponent of the disease as an 
entity, deserves great credit for his work on hepatic sider- 
osis, emphasized the importance of glossitis as a diag- 
nostic sign, and has written two valuable monographs on 
the disease. The first—Pernicious Anemia, London, 1901 
—reviewed the literature very thoroughly, demonstrated 
hepatic siderosis, advanced many arguments in favour 
of an infective and gastro-intestinal hypothesis, and pre- 
sented many pathological and clinical observations. The 
second—Severest Anaemias, vol. 1, London, 1909—dis- 
tinguished idiopathic from septic anaemias. He construed 


28 PERNICIOUS ANEMIA 


the former as a specific, infective hemolytic disease, ag- 
gravated by an added (and predisposing) element of 
sepsis. He minutely described the glossitis. After an 
analytical review of the literature he deprecated the term 
“pernicious” and advocated the name Addisonian ane- 
mia. From a practical standpoint, oral sepsis, even aside 
from its bearing on anemia, stands, as a conception and 
a proved reality, largely to the initial credit of William 
Hunter. On the other hand, few believe that glossitis is 
constant as he maintains and no one has confirmed his 
statement of the importance of unsanitary drains in the 
etiology; it will be pointed out that he entertained the 
ideas of Cohnheim and Ehrlich almost as little as Ehrlich 
entertained Hunter’s, and it should be finally stated that 
Hunter never presented any really convincing reasons for 
faith in his often repeated dogma that pernicious anemia 
is a specific infection. The remarkable quality of Hunter 
has been his sustained enthusiasm, and his greatest serv- 
ice, as the writer sees it, lies in this—that he gave a 
powerful impulse to the study of features other than 
hematological. 

That a confusion of almost indecipherable character 
should have marked the first forty years of our knowledge 
of this disease is not remarkable. In view of the confusion 
which still exists after seventy years, it may be character- 
ized as inevitable. The haziness of earlier conceptions, the 
false interpretation of symptoms as causes, the variety of 
nomenclature, the divergence of definitions, and the con- 
flict, therefore, of rival classifications all tended to pro- 
duce confusion. After Addison’s description, the tendency 
of English clinicians was to exclude all cases in which 
any evident cause could be detected. This bred an attitude 
that the anemia was primary and essential, and that all 
the manifestations of the disease, as then recognized, 
were the result of the blood impoverishment. Today, of 
course, such a position is untenable, and the blood state 


HISTORICAL OUTLINE 29 


must be regarded as but one result of the still unknown 
fundamental process. Opinion being as it was then, any 
new discovery, such as bone-marrow changes (Pepper, 
Cohnheim) or atrophy of the stomach (Fenwick, Osler, 
Kennicutt) was not readily included among the mani- 
festations of the disease but used as reasons for exclud- 
ing the cases described from the pure “primary” class. In 
other words, there was a tendency to attach etiological 
significance to any important pathological observation 
and to regard such observed cases as of a “‘secondary” 
nature. Again, not only did American and English phy- 
sicians suffer from this confusion incidental to growth of 
knowledge, but they began applying the continental epi- 
thet “pernicious” even to their purest cases of Addison’s 
anemia, whereas the Germans and Swiss used this name 
for any severe macrocytic anemia whether or not the 
cause was apparent. To all this was added the uncertainty 
which the remissions impose on the interpretations of 
treatment. The net result was the most glaring and sus- 
tained confusion which has ever clouded the history of a 
disease. It became an international medical pastime to 
exclude cases from published reports on the basis of 
purity of type, each critic employing his own individual 
or local standards of judgment. The cure for all this was 
more knowledge, and the cure came slowly. 

In 1891 Ehrlich practically created hematology a sci- 
ence by the discovery of the value of aniline dyes for 
staining blood smears. From this time dates accurate 
information of the blood picture. Ehrlich became especi- 
ally interested in megaloblasts (large nucleated erythro- 
cytes) and initiated the school of megaloblastic degener- 
ation, the chief tenet of which is that marrow degeneration 
of a megaloblastic type constitutes the essential process 
in this anemia. This was a step further than Cohnheim 
had gone in regarding the marrow condition as a rever- 
sion to an embryonic type of blood formation. Muir 


30 PERNICIOUS ANEMIA 


(457) in 1894 made a study of the bone marrow, and 
interpreted the findings as caused by an exorbitant regen- 
erative effort to compensate for the loss of destroyed cor- 
puscles. His mind was impressed previously by Hunter’s 
contention that blood destruction was effected in the portal 
circulation by poison absorbed from the intestine. The 
view-point adopted by Hunter and by Muir, viz., that the 
marrow changes were purely of a compensatory character, 
has had a tremendous and lasting influence. A definite 
Ehrlich school remains on the continent today and regards 
the marrow changes as fundamental to the anemia, and 
caused by a “noxa”’ from the gastro-intestinal tract. 

The nervous features began to be recognized about 
1884, but further description of the growth of our knowl- 
edge of the changes will be withheld until a later chapter. 

The present century has established the almost invari- 
able association of achlorhydria with the disease, in- 
creased our knowledge of the pigment condition, made 
distinctions in the blood picture from similar anemias, 
rendered all the clinical features familiar, and facilitated 
diagnosis. Etiologically, several definite hypotheses have 
been worked upon and the intestinal flora has been exten- 
sively studied. Final and unfavorable judgment has been 
passed upon splenectomy in treatment, and blood trans- 
fusion is recognized for its limited value. It must be 
admitted that the entire field of pernicious anemia has 
been particularly barren of results. Recently the observa- 
tions on the effects of liver diet have been sufficiently 
startling to arouse a new and widespread interest in the 
disease. 


CHAPTER III 
ETIOLOGY 


HISTORICAL ETIOLOGICAL CONCEPTIONS 


Combe (128), who described the first recorded case, 
saw no cause whatever, but suspected the digestion and 
assimilation of food. Elliotson (171) wavered between 
an ill-defined notion of gravitational or emotional effect 
and one of a change to white-bloodedness. Addison (5), 
who enjoyed the somewhat unique distinction of having 
propounded no hypothesis, merely wondered if fatty de- 
generation had anything to with it. Fenwick (199) con- 
sidered the degenerative changes in the gastric mucosa 
to be significant. Perroud (496) attributed the whole 
complex to fatty degeneration of the liver. Biermer (60) 
felt that even in his cases of idiopathic origin, sufficient 
cause could be seen in the bad hygienic conditions, or in 
the diarrhoeas of his patients. The only lesions he could 
associate etiologically were ulcers of the colon. Mackenzie 
(390) believe that neurosis was a definite factor. Cohn- 
heim (123), Ehrlich (163), and with them most of the 
early continental observers, regarded the marrow condi- 
tion as the cause of the anemia. The English school and 
many European authorities came to believe that blood 
destruction of abnormal degree was the means of blood 
depletion, and that the marrow changes were regenerative 
and compensatory. 

The early bone marrow observations of Pepper (493), 
of Cohnheim (123), and of Osler and Gardner (480) 
resulted in emphasis being placed upon the abnormal type 
of blood formation seen and in the noting of phagocytosis 
of red blood corpuscles in this tissue. Ehrlich became espe- 
cially interested in the presence of megaloblasts in the 
marrow and the circulating blood. Whereas Cohnheim 


[ 31] 


32 PERNICIOUS ANEMIA 


had been content to regard the marrow changes as a rever- 
sion to an embryonic type of blood formation and as of 
primary significance in the etiology, Ehrlich went a step 
further and conceived the marrow changes as degener- 
ative in nature. This hypothesis of megaloblastic degen- 
eration, rendered vivid by its author’s classical stains of 
the blood tissues, substantially implanted itself in the 
minds of Ehrlich’s contemporaries and has exerted a pro- 
found influence even to the present day. Ehrlich held up 
the megaloblast as a simple and infallible point in the 
diagnosis of pernicious anemia and he embraced the inevi- 
table and logical corollary that all anemias showing mega- 
loblasts were pernicious anemia. This classification placed 
megaloblastic anemias in a primary group and normo- 
blastic anemias in a secondary group, and ran parallel to 
Biermer’s clinical classification, which permitted the term 
pernicious anemia to be extended to several severe 
anemias of known etiology. 

The English school, before and during Ehrlich’s 
studies, had developed a different view-point. Of first 
importance to the English investigators was an exclusive 
definition of the disease. Following in Addison’s foot- 
steps, they applied the term pernicious anemia only to 
cases of idiopathic origin, and excluded all cases, in spite 
of the blood picture, in which any cause was evident. To 
them pernicious anemia was, at that time, largely a dis- 
ease of the blood. The anemia was primary and uncaused, 
and all other manifestations were the results of the 
anemia. This fixed idea resulted commonly in the misin- 
terpretation of newly discovered pathological facts. Suf- 
ficient reference has already been made, in the previous 
chapter, to the unfortunate and almost hopeless confusion 
which resulted. 

In any synoptic review of this most involved period 
(1870-1900), one must recognize the stabilizing effect of 
the work of Hunter, although it failed in its entirety to 


ETIOLOGY 33 


achieve the conclusive results which, in its beginning, it 
might seem to have promised. Its stabilizing effect lay 
chiefly in its direction toward other than purely hemato- 
logical studies. Hunter (290-302) emphasized the clinical 
signs and symptoms of the digestive tract. Particularly his 
careful work on hemosiderosis of the liver has exerted a 
far-reaching effect on subsequent thought. Briefly he 
demonstrated by gravimetric analysis that the liver in 
pernicious anemia contains more iron than the liver in 
other anemias. Siderosis had been little observed on the 
continent and, when found, had been frequently dis- 
missed as due to iron medication and of no constant or 
specific importance. Hunter, on the other hand, held up 
hepatic siderosis just as stoutly as Ehrlich has held up 
the megaloblast, as an alleged specific finding. Then Hun- 
ter by a process of synthetic thought, which has always 
impressed the writer as at once natural but unwarranted, 
supposed this deposit of iron-bearing pigment in the liver 
was the result of abnorma. blood destruction in the portal 
area. (It should be noted, in passing, that the more recent 
experimental work of McMaster, Rous, and Larimore 
(420) makes it seem probable that liver siderosis does 
not connote any specific bodily site for blood destruction. ) 
Hunter believed that a toxin, probably produced by a 
specific micro-organism in the lumen of the intestine, was 
being absorbed into the portal blood and was there caus- 
ing an intense destruction of blood corpuscles, the freed 
pigment from which was then deposited in the liver 
lobules. However little or much of truth may be contained 
in this hypothesis, it was the first, and it was a daring at- 
tempt to explain the anemia by extensive blood destruc- 
tion. Muir’s (457) study of the bone marrow in 1894, 
largely confirmed the morphological findings of the earlier 
investigators. But Muir, having been impressed by Hunt- 
er’s insistence on the importance of alleged portal blood 
destruction, found it possible to interpret the marrow 


34 PERNICIOUS ANEMIA 


changes as a very extensive and energetic regeneration 
undertaken in response to a severe bodily demand for 
blood. 

Thus were established two contending schools of 
thought. The one, initiated by Cohnheim and led by Ehr- 
lich, taught that the anemia was due to a primary altera- 
tion in the marrow, of the nature of an embryonic 
reversion, or, otherwise expressed, of a megaloblastic 
degeneration. This school approached the subject from 
an almost purely hematological angle. The other, initiated 
by Hunter, and supported not only by Muir but later by 
Askanasy and other European students, taught that 
abnormal blood destruction was the essential funda- 
mental process, and that the extreme marrow changes 
were to be regarded as a compensatory regenerative 
activity in response to an urgent physiological need. This 
school approached the subject from a physiological and 
clinical, as well as a hematological angle. 

Many observers, notably Mott (456), Henry (264), 
Russell (542), and Earl and Purser (159), while willing 
to admit abnormal blood destruction to a degree, believed 
that it depended upon the circulation being presented 
with inadequately formed corpuscles. They therefore 
regarded abnormal blood formation as fundamental, and 
abnormal blood destruction as a consequence. 

The importance of the digestive system became appar- 
ent through the combined work of Fenwick (199), Flint 
(205), Barclay (22), Hunter, and others during the 
period 1852-1890, with particular emphasis on the 
atrophy of the gastric mucosa, the specific glossitis, and 
the familiar train of gastro-intestinal symptoms. From 
1884 onward to the present, the importance of the nerv- 
ous system has become increasingly clear, owing to the 
work of some fifty observers. Whereas until the early 
nineties the disease was regarded generally and chiefly 
as a blood disease, it is now of necessity regarded as a 


ETIOLOGY 39 


much wider tissue involvement, the blood features being 
but one of these outstanding system changes. 

Within the historical period, as here briefly outlined, 
may be detected the issues which remain today. The chief 
issue is the problem of the relative importance of abnor- 
mal blood destruction and abnormal blood production. It 
is a problem involving a close scrutiny of all the hemato- 
logical data in our possession. It further involves an etio- 
logical evaluation of other manifestations of the disease, 
of other possibly related factors, a comparison with simi- 
lar clinical anemias, and a critical review of experimental 
findings. 


EVALUATION OF THE HEMATOLOGICAL DATA 
The typical, full-established blood condition is a very 
severe anemia of which marked oligocythemia and com- 
plete corpuscular complement of hemoglobin are two 
characteristic features. Morphological alterations in the 
red blood cells stand out as the most highly characteristic 
feature. A marked degree of anisocytosis, rendered so 
graphic by the now familiar Price-Jones (503) curves, is 
constantly present and depends upon the presence par- 
ticularly of macrocytes and megalocytes and also, but to 
a less degree, of microcytes. The macrocytes are, more- 
over, characteristically of an oval rather than a circular 
outline. Among the cells of normal or subnormal size, 
poikilocytosis is commonly present in a more or less 
marked degree. The shapes exhibited are somewhat char- 
acteristic of the disease, viz., forms resembling Indian 
arrow-heads, Grecian urns, dumbells, as well as unsym- 
metrical figures impossible to describe. The white blood 
cells are reduced in number, with absolute reduction in the 
polymorphonuclear neutrophils. The blood platelets are 
markedly reduced in number. 
Nucleated red blood cells—normoblasts and megalo- 
blasts—while characteristic and to some degree diagnostic 


36 PERNICIOUS ANEMIA 


when found, occur much less frequently than formerly 
taught. In the blast crises, when occurring in high per- 
centage, they are not usually of good prognostic signifi- 
cance, although when occurring in lesser numbers, 
especially in conjunction with increased numbers of 
reticulocytes and polychromatic corpuscles, they are of 
good prognostic significance. 

The disturbed state of the bile-pigment metabolism is 
evident from the hyperbilirubinemia, the increased output 
of urobilinogen and urobilin by the liver, and the increased 
output of urobilin by the kidneys. The bilirubin of the 
blood is apparently fixed in some physico-chemical union 
with the plasma proteins, so that it does not readily dialyze. 
Van den Bergh (618) has shown that this plasma biliru- 
bin behaves differently in the diazo-reaction from the bili- 
rubin associated with hepatic obstruction or disease. The 
peculiar jaundice of grapefruit hue, when present, is due 
to staining of the tissues by this bilirubin. Blankenhorn 
(48) shows that hyperbilirubinemia may sometimes be 
present without jaundice. Moreover, considerable anemia 
may be present without any marked hyperbilirubinemia, 
but, as a rule, severe anemia is accompanied by a marked 
increase of this pigment in the plasma. Minot (440) has 
found that the simple observation of the degree of stain- 
ing of the plasma is a fair index to the severity of the 
anemia and may be rendered of comparative value by 
determining how much water must be added to the plasma 
to cause the color to disappear. 

The increased loss of bile-pigments by the stools and 
the urine is very tangible evidence of disturbance of the 
pigment metabolism. 

The siderosis of liver, spleen, and kidney, the latter 
betrayed by siderosed cells in the urinary sediment, indi- 
cates disturbance in the metabolism of iron-containing 
pigment. These features as well as the fact that the red 
blood cells, however large, are normally filled with hemo- 


ETIOLOGY af 


globin, indicate that the body is overcharged with iron 
pigment. Free hemoglobin may be detected in the serum 
and occasionally in the urine in severe stages. Sellards 
and Minot (570) have shown that patients with perni- 
cious anemia will excrete hemoglobin in the urine when 
injected intravenously with doses of an aqueous solution 
of this pigment which cause no such excretion in nor- 
mal individuals or in patients with anemia following 
hemorrhage. 

Peabody and Broun (489) made a comparative study 
of the vertebral bone-marrow in pernicious anemia and 
other diseases as well as in normal persons killed by trau- 
matism, with special attention to the phagocytosis of the 
red corpuscles by the clasmatocytes. They found in 
pernicious anemia bone marrow a degree and an acuteness 
of phagocytosis, sufficient to suggest that this process of 
blood destruction may be a factor in the production of 
the hyperbilirubinemia. 

Custom during the past twenty years has classified 
the hematological data in somewhat the following 
manner: 


A. Evidences of abnormal blood destruction :—the 
oligocythemia, the small microcytes, fragmented 
erythrocytes, the phagocytosis of corpuscles by the 
clasmatocytes, the deposits of iron pigment, and the 
abnormal features of the bile-pigment metabolism. 

B. Evidences of abnormal blood formation :—the mac- 
rocytes and larger microcytes of the circulation, as 
well as the occurrence of nucleated red blood cells, 
especially megaloblasts. 

C. Evidences of blood regeneration:—the occurrence 
of immature red blood cells (polychromatic cyto- 
plasm, nucleated forms, reticulocytes) and rising 
figures both for the red blood cell count and the 
hemoglobin percentage. 


38 PERNICIOUS ANEMIA 


One of the most striking statements which it is pos- 
sible to make in connection with the problem of blood 
destruction in this disease is as follows—the only site 
and the only mechanism of blood destruction which has 
been demonstrated is the phagocytosis by the clasmato- 
cytes of the reticuloendothelium in the bone marrow. 
Osler (479) could not suppose this to be of any specific 
importance since he observed an apparently equal degree 
of phagocytosis in the marrow in some cases of pneu- 
monia. Peabody and Broun (489) found a very abnor- 
mal increase in phagocytosis in certain cases dying of 
hepatic cirrhosis, pneumonia, typhoid fever, and tuber- 
culosis. The most marked instances, however, were en- 
countered in patients dying in the acute stage of pernicious 
anemia. On the other hand, in the case of a patient dying 
in a remission of this disease, phagocytosis of red blood 
corpuscles was not a striking phenomenon. 

The problem of whether the erythrocytes so engulfed 
are effete or specially marked for destruction, is not set- 
tled. The phagocytosis is apparently an acute and active 
process because hemosiderosis, characteristic of a more 
sluggish phagocytosis, is practically absent, according to 
Peabody and Broun, in the marrow of the pernicious 
anemia. 

The greater problem as to whether or not this phago- 
cytosis can account for the degree of oligocythemia pres- 
ent is also impossible to settle, but from comparison with 
other diseases, in which great phagocytosis occurs with- 
out a corresponding degree of oligocythemia, the answer 
may be temporarily given in the negative. 

The degree of biliruminemia corresponds roughly, and 
in a direct manner to the degree of oligocythemia, so that 
both are greatest and both are least at the same times in 
the disease. As the erythrocyte count and hemoglobin 
percentage rise in a remission, not only does the degree 
of bilirubin in the plasma decrease, but there appear the 


ETIOLOGY 39 


accepted evidences of regeneration, and the red blood 
corpuscles show a more normal type of formation. These 
facts are demonstrated very beautifully by Murphy, Mun- 
roe, and Fitz (463) in connection with remissions caused 
by liver diet. Conversely, when a relapse occurs, the bili- 
rubinemia increases, and the red blood corpuscles exhibit 
increased evidence of abnormal formation. There is there- 
fore generally to be noted a somewhat indivorcible rela- 
tionship among the three features which custom has 
separately recognized—abnormal destruction, abnormal 
formation, and regeneration. 

As Archibald (13) and as Minot and Lee (446) have 
pointed out, it is possible to recognize five somewhat dis- 
tinct types of the disease, depending upon the balance 
maintained between blood destruction and blood produc- 
tion. In the first there occurs a rapid unremitting course 
with oligocythemia, a marked degree of abnormal blood 
formation and of bilirubinemia. In the last there occurs a 
long monotonous course with much evidence of abnormal 
blood formation and a less degree of bilirubinemia—the 
so-called myelotoxic cases. Between these extremes there 
lie three types of remitting cases. The middle type of the 
five is one in which may be synchronously observed evi- 
dences of abnormal formation, hyperbilirubinemia, and 
the appearance of immature forms. It is this type of case 
particularly which suggests that an abnormal state of the 
marrow might explain the whole blood condition. Minot 
remarks that this type of pernicious anemia bears a defi- 
nite resemblance to acquired hemolytic jaundice. 

The two crucial questions emerging from these con- 
siderations are as follows: (a) Is the marked oligocy- 
themia the result chiefly of abnormal blood destruction or 
insufficient blood production? (b) Does the disturbance 
of the pigment metabolism indicate blood destruction, and, 
if not, what is its exact significance ? 


40 PERNICIOUS ANEMIA 


Whipple (646) as well as Ashby (19) have questioned 
the importance of blood destruction in pernicious anemia. 
The former has advanced an hypothesis with the purpose 
of indicating that the time-honored viewpoint of the 
essential importance of blood destruction may, not with- 
out reason, be modified. In brief, his hypothesis is that 
the oligocythemia is due to insufficient blood cell form- 
ation depending upon insufficient available stroma mate- 
rial and that the disturbed pigment metabolism is due to 
an overstimulation resulting in more pigment being 
formed than can be used. 

The work of Whipple and Hooper (647), McNee 
(422), Van den Bergh and Snapper (621), and of Mann 
et al. (397, 398, 399) indicates that in addition to the liver 
parenchyma, the reticulo-endothelium both in the liver 
and elsewhere, as well as vascular endothelium and serous 
mesothelium generally, not only can, but constantly do, 
metabolize hemoglobin into bilirubin. Whipple suggests 
(645) that the liver parenchyma and the Kupffer cells 
may be able to reverse their function and form hemo- 
globin from bilirubin. Doan, Cunningham, and Sabin 
(150) could actually witness hemoglobin being assembled 
in the megaloblasts of the bone marrow. Their work indi- 
cates that the megaloblasts are actually daughter cells of 
the reticulo-endothelium. Due reflection upon these sev- 
eral points suggests the possibility that in pernicious 
anemia the total hematological manifestations may result 
from abnormal cell metabolism on the part of the reticulo- 
endothelial system. It is much too soon to make more than 
the suggestion, but, in this connection, the recent nutri- 
tional work of Barker and Sprunt (25), of Mosenthal 
(454), of Gibson and Howard (223), and of Minot and 
Murphy must be considered. A detailed study of these 
papers suggests that the feeding of certain as yet unde- 
termined food principles brings about a complete reversal 
of a blood relapse into a blood remission and makes it 


EP MOLOGY Al 


appear not impossible that the blood phenomena of per- 
nicious anemia are due immediately to the absence of 
certain factors of nutrition, essential to the normal metab- 
olism of the productive cells of the bone marrow. 

The bone marrow in pernicious anemia shares the 
unsatisfactory state of normal marrow studies. Exten- 
sion of the red marrow and marked erythroblastic 
activity are well recognized, but as Archibald (14) and 
as Sheard (576) have indicated, this regenerative activity 
is not necessarily, and perhaps never, a universal phe- 
nomenon affecting all the bone marrow of the individual. 
Sheard’s investigations suggested that active regenera- 
tion was most liable to occur in those parts of the marrow 
not normally active. The prominent histological feature 
of this active marrow is the large number of nucleated 
red blood cells, which may constitute up to 25 per cent of 
all cells present. We recognize megaloblasts, erythro- 
blasts, and normoblasts. The non-nucleated red corpuscles 
exhibit the same size variations as are found in the gen- 
eral circulation, none being so large as the megaloblasts 
but many paralleling in size the erythroblasts. Many of 
the clasmatocytes lining the sinuses may be seen phagocy- 
tosing red corpuscles, most of which contain hemoglobin. 
The marrow shows very little siderosis. Zadek’s (668) 
claim to have demonstrated a return to fatty marrow 
during remission is not perfectly sound. 

The spleen may be regarded as playing a role sub- 
servient but not essential to the disease. Splenectomy, in 
addition to causing certain metabolic changes and a 
greater delivery of immature marrow cells, does little to 
prolong life in the majority of cases. Histologically the 
spleen presents a combined picture of sclerosis, siderosis, 
and phagocytic activity, the pulp containing many red 
blood cells showing poikilocytosis and fragmentation. 
The uncommon cases with splenomegaly may represent a 
somewhat distinct type of the disease and do well follow- 


42 PERNICIOUS ANEMIA 


ing splenectomy provided the operation is performed 
sufficiently early. 

The not infrequent enlargement of the liver coincides 
with the accepted signs of increased blood destruction. 
The liver presents a more extreme example of siderosis 
here than in any other disease. Fatty degeneration varies 
from moderate to extreme and affects chiefly the centres 
of the lobules. Kahn and Barsky (331) found the glyco- 
genic and ureogenic functions normal, as also the func- 
tions as tested by Bauer’s galactose and Strauss’s levulose 
tests, while the sulpho-conjugation test indicated a de- 
ficiency in detoxication function. 


ETIOLOGICAL EVALUATION OF OTHER MANIFESTATIONS 


Among the manifestations, other than hematological, 
which appear to bear a specific relationship to the disease, 
the following are to be particularly designated :—glos- 
sitis, achlorhydria, nerve tissue degeneration, the fatty 
changes, and the remissions. In addition, the general 
metabolism requires description. All other symptoms and 
signs will be purposely neglected, in this chapter, as not 
bearing either constant or apparent relationship. 

What is written of this glossitis may be applied to the 
stomatitis, pharyngitis, oesophagitis, and even gastritis 
which, judging from symptoms, may co-exist as the 
apparent extension of the same process. Noted first by 
Barclay in 1852 and its incidence later somewhat over 
emphasized by Hunter, the glossitis is now granted a spe- 
cific relationship to the disease. No one except Percy 
(495) has supported Hunter’s contention that glossitis 
occurs in every case. Panton, Maitland-Jones, and Rid- 
doch (482) found it in 25 per cent or slightly higher. In 
the early active stages the tongue, always clean and moist, 
may present a fiery red or carmine hue, a painfully fis- 
sured dorsum, and sometimes vesicles containing serum. 
Later, when the organ is anemic, the glossitis is manifest 


ETIOLOGY 43 


chiefly by a mottled red appearance along the borders or 
in patches of hyperemia on the surfaces. Small ulcers 
may be seen. In the final stages of the disease the process 
is usually less noticeable and the tongue presents, in gen- 
eral, an ironed-out, atrophic appearance. The papillae are 
dwarfed or absent. Even when thus comparatively quies- 
cent, the glossitis may recur in periodic attacks of sore- 
ness and marginal redness even in late stages. In patients 
with very long remissions of the disease, the atrophic 
tongue remains as a permanent hall-mark, of equal sig- 
nificance to the permanent macrocytosis which has like- 
wise been frequently noted. 

The glossitis is troublesome in varying degrees in 
different cases showing it, and interferes with eating, 
sometimes with sleeping. It is not infrequently the initial 
symptom of the disease. Local treatment fails to benefit 
it. During the disease if is characterized by an irregular 
periodicity. A troublesome glossitis reappearing or recru- 
descing during a remission often indicates the nearness 
of a relapse. 

At autopsy the tongue shows the gross and microscopic 
features of a combined mucosal and muscular atrophy. 
At points where the mucosa has disappeared a round cell 
infiltration will be found in the submucous tissues. In very 
severe cases a great proportion of the muscular fibres are 
replaced by fatty connective tissue. Hunter obtained from 
the interior of such tongues pure cultures of a virulent 
long streptococcus and considered this micro-organism to 
be responsible for at least part of the glossal manifesta- 
tions. The periodicity of the symptom, glossodynia, sug- 
gests that any causative micro-organism would be one 
characterized by its tendency not only to crudesce and 
subside, but also to migrate downward and cause the 
oesophagitis and gastritis so frequently associated. No 
specific micro-organism has been isolated from the tongue 
lesions. The nature of the glossitis is obscure. Faber 


44 PERNICIOUS ANEMIA 


would interpret the glossitis as due to a chronic toxemia 
with a hypothetical poison responsible at once for all the 
digestive, nervous, and blood abnormalities. It is of inter- 
est to recall the occurrence of glossitis in sprue and 
pellagra, between which two forms Woods notes a great 
difference, and both of which differ from that of perni- 
cious anemia. No one has definitely noted glossitis in so- 
called “pure” cases of subacute combined degeneration of 
the cord, but it is thought to occur in these cases even in 
the absence of blood changes. 

Achlorhydria. Cahn and von Mehring (94), von 
Noorden (624), Einhorn (166), Stewart (594), Gra- 
witz (220), Martius (406), and others were first respon- 
sible for the clinical examination of the stomach contents, 
1886-1897, and for thus affording to medicine a physio- 
logical means of study which has since proved of greater 
value than anatomical or histological means, especially 
with reference to pernicious anemia. Grawitz in the late 
nineties listed “achylia gastrica” as an etiological factor 
in the broad group of cases which he, in conformity with 
continental custom, included under the term pernicious 
anemia. Among Martius’ seventeen cases of achylia, 
reported in 1897, two died of pernicious anemia and 
showed, post mortem, pronounced atrophy of the gastric 
and intestinal mucosa. He took the attitude that while 
arrest of gastric secretion arising from mucosal atrophy 
can lead to some degree of anemia, the essential lesion 
was intestinal mucosal atrophy operating by disturbance 
of food absorption. Faber and Bloch (185) in 1900 col- 
lected thirty-three cases of the disease in which the gas- 
tric contents had been examined and in all of which it had 
been found either greatly diminished or entirely absent. 
Similar results were obtained in their own four cases, 
two of whom showed, post mortem, diffuse inflammation 
of the stomach wall with destruction and atrophy of the 
glands. They found no constant or characteristic lesion 


ETIOLOGY 45 


of the intestines, believing that the appearances of atrophy 
there discovered were artificially produced by post mor- 
tem distension of the gut. While Faber has never com- 
pletely repudiated the position which he then adopted, 
viz., that the stomach changes and the blood changes have 
a common cause, whether of toxic or infective nature, he 
recently gives some acceptance to the conception of the 
achlorhydria being a constitutional phenomenon. 

Hutchison (312), in reviewing the subject in 1909, 
showed that as valuable as the many gastric observations 
had been, belief in the stomach condition as the cause of 
pernicious anemia was rendered untenable by the accumu- 
lating evidence of achylia existing for years without 
blood changes. He favored the view that the achylia, by 
robbing the intestinal tract of its normal antiseptic, may 
predispose to pernicious anemia, and was among the first 
definitely to recommend dilute hydrochloric acid as a 
rational form of treatment. 

With the introduction of the Einhorn, the Rehfuss, and 
the Ryle tubes, and the fractional test meal, many gen- 
eral cases considered achlorhydric were discovered to 
secrete free HCl at some phase of the digestive period. 
But patients with pernicious anemia, even when exam- 
ined by this improved technique, were still found, almost 
invariably, to secrete no free HCl at any time. A few 
isolated instances have been reported in which some 
free HCl was detected during digestion in cases appar- 
ently justifying the diagnosis of pernicious anemia. In 
some cases, autopsy examination proved conclusively that 
they were not pernicious anemia. 

All investigators of the gastric secretion in this dis- 
ease have been convinced of the almost constant occur- 
rence of achlorhydria. Many reports confirm this opinion, 
particularly that of Levine and Ladd (370) who, in a 
series of one hundred and fifty cases by the use of the 
fractional meal, found achlorhydria in ninety-nine per 
cent. Hurst (307) is in accord with this finding. Faber 


46 PERNICIOUS ANEMIA 


and Gram (186) in fifty-four cases studied between 1907 
and 1922 found achlorhydria in fifty. Piney (499) has 
seen one case of subacute combined degeneration of the 
cord without achlorhydria. But Hurst and Bell (311) 
have shown that achlorhydria is as common in “pure” 
cases of combined degeneration as in cases showing the 
specific anemia. Panton et al. (481) reported achlorhydria 
in all of one hundred and seventeen cases of pernicious 
anemia. Shaw (575) presénted a case unique because of 
recovery not only from the disease but from alchlorhydria. 
Percy (495) found free HCl in but one of one hundred 
and twenty-nine cases. If one fact has received ample 
confirmation in connection with the whole subject of 
pernicious anemia it is this—the stomach contents almost 
never contain free HCI. 

Furthermore, so far as critically reported, achlorhydria 
precedes all other symptoms of pernicious anemia. Faber 
examined the blood in four cases, as many as twelve 
years before pernicious anemia developed, and while the 
hemoglobin percentages were all between ninety and one 
hundred, achlorhydria was definitely present. Riley (526) 
has reported two cases in which achlorhydria was present 
twenty and twenty-five years respectively before the onset 
of the disease. Other instances have been collected by 
Hurst: in two cases achlorhydria was discovered twelve 
years (Bie (59), Gross (237) ); in another ten years 
(Wilkinson); in another seven years (Faber (182), 
Cobet and Morawitz (120) ); six years (Levine and 
Ladd (370) ); five years (Kuttner (350) ); three years 
(Faber, Wilkinson) ; two years (Charles Hunter (286) ) ; 
and one year (Levine and Ladd) before the inception of 
pernicious anemia. Not one case has been reported of any 
individual, then suffering from true pernicious anemia, 
who, prior to the disease, was even demonstrated to have 
a normally functioning gastric mucosa. 


ETIOLOGY 47 


The condition of achlorhydria as it occurs in pernicious 
anemia, is, moreover, as permanent and usually more 
permanent than the disease, and does not alter with 
remissions however long, or with any form of treatment 
yet employed. The one exception to this rule is illustrated 
by the case of Shaw’s. Even in three remissions of sev- 
enteen to twenty years’ duration, seen by Hurst (310), 
the introduction of the Ryle tube has led invariably to the 
same finding—persistent achlorhydria. 

Achlorhydria not associated with pernicious anemia 
may show in some instances some degree of recoverability, 
as demonstrated by Hurst in alcoholic achlorhydria. 

But an achlorhydria of alcoholic origin may progress 
to a permanent condition and predispose to pernicious 
anemia, as may also the achlorhydria associated with 
cirrhosis of the liver. 

It becomes possible to imagine that of the whole group 
of pernicious anemia, the attendant achlorhydria may be 
either one of two types—constitutional or acquired. In 
such a grouping the acquired forms might be listed as 
follows:—(1) Alcoholic achlorhydria. (2) The achlo- 
rhydria resulting from gastro-enterostomy. Hurst (307) 
found a case at Guy’s Hospital illustrating this syndrome, 
but achlorhydria due to regurgitation of alkaline jejunal 
contents might be apparent rather than real. (3) The nec- 
essary achlorhydria resulting from complete gastrectomy. 
Hurst (307) knows of five cases in which pernicious 
anemia followed extirpation of the stomach. As Piney 
(499) pointed out, since this operation is usually under- 
taken for carcinoma, any subsequent alleged pernicious 
anemia would require to be studied carefully with special 
intent to rule out a secondary deposit of carcinoma in the 
bone marrow. (4) The achlorhydria of gastric carcinoma. 
The fractional method in cases of stomach cancer shows 
achlorhydria in fifty per cent, although in the other fifty 
pet celit the amount of free) HCl is greatly reduced: 


48 PERNICIOUS ANEMIA 


Hurst (307) has seen typical subacute combined degen- 
eration of the cord associated with cancer of the stomach, 
in which achlorhydria was present. Clinicians are all 
familiar with the occasional association of pernicious 
anemia with cancer of the stomach, although this double 
diagnosis must be made with care, since there occurs a 
macrocytic but not Addisonian anemia not infrequently 
in such cases. 

One may accept as bona fide all such cases of pernicious 
anemia occurring in instances where the achlorhydria 
might be conceived of as being acquired, yet a major ob- 
jection remains to admitting acquired achlorhydria as a 
predisposing cause of pernicious anemia. The instances 
reported are so few that this group might be supposed 
to have been potential victims of pernicious anemia in the 
course of ordinary events, and there is no proof that they 
did not have achlorhydria previous to those events from 
which they are credited with having acquired it. The bal- 
ance of collected evidence favors the view that the achlor- 
hydria of pernicious anemia is a condition long antedating 
the beginning of the disease. 

Among the causes which have been alleged for this 
achlorhydria may be noted the following: (1) The 
anemia. This conception grew up during the initial con- 
fusion of the subject, but has been completely set at rest 
by facts already set forth, viz., that the achlorhydria 
antedates the anemia and persists, unaffected, during long 
periods of blood improvement. In Hurst’s (307) gastric 
studies in cases of hemorrhagic and other simple anemias, 
the curve of secretion was found perfectly normal. (2) 
The toxic or infective processes which likewise cause the 
other symptoms of the disease. In the light of this theory 
the achlorhydria is the functional result either of a toxic 
parenchymatous gastritis due to the prolonged insult of 
small concentrations of toxin over a long period, and 
therefore parallel to our conceptions of other parenchy- 


ETIOLOGY 49 


matous intoxications; or, of an interstitial infectious 
gastritis resulting, by condensation of fibrous tissues, 
eventually in atrophy of the secreting cells. In favor of 
this theory is the fact that from twenty to thirty per cent 
of patients show a prodromal debility for years previous 
to the disease, and characterized by marked digestive dis- 
turbances. Against it is the fact that seventy per cent of 
patients have been healthy previously, and the very perti- 
nent fact that gastric atrophy may not be present. (3) 
Constitutional factors of unknown nature. This hypothe- 
sis supposes that aclorhydria is a functional phenomenon 
not necessarily associated with any gastritis. The biopsies 
of Hurst and Passey revealed that the gastric mucosa in 
pernicious anemia may be histologically normal although 
achlorhydria was present. In some cases at least, there- 
fore, we have the phenomenon of normal architecture 
associated with absence of function. Again, as Hurst 
(307) has reasonably argued, a non-functioning gastric 
mucosa is, for several reasons, more liable to secondary 
injury than a functioning one. Food matter fails to receive 
the normal gastric maceration and is hence more liable to 
cause mechanical irritation. The mucosa, robbed of its 
normal antiseptic defence, is prone to infection from bac- 
teria-laden food and saliva from the notoriously unhealthy 
mouth. 

The theory regards the achlorhydria of pernicious 
anemia as caused by some “primary” fault, perhaps some 
constitutional and even inherited abnormality. It regards 
the manifestations of gastric sepsis as due to secondary 
injury and invasion. That a constitutional or even heredi- 
tary factor may be all important, is strongly suggested by 
the study of true instances of familial pernicious anemia. 
In such instances the only tangible link between affected 
blood relatives is the achlorhydria. Hurst (307) phrases 
this the “achlorhydric gastric diathesis” and recites many 
instances of achlorhydria in the blood relatives of per- 


50 PERNICIOUS ANEMIA 


nicious anemia patients. In some instances an absence of 
gastric secretion has been found in patients’ children as 
young as six and four years of age, thus strongly sug- 
gesting that the condition is an inherited one. 

While clinical study has not elucidated the cause of 
achlorhydria it has distinguished between it and the con 
dition properly named achylia gastrica. In England and 
North America the former term, and on the continent 
the latter term, are used somewhat promiscuously to indi- 
cate either condition. The distinction between the two is 
apparent from the following definitions. Achlorhydria is 
a condition in which, by the use of the fractional test 
meal, no free HCl is detected in the stomach contents dur- 
ing either the digestive or interdigestive period, although 
combined acid and some degree of peptic activity may be 
found. Achylia gastrica is a condition in which, when 
similarly examined, neither free or combined HCl is 
detected at any period and peptic activity is lacking. The 
latter definition, if desired, may be rendered more strict 
by specifying lack of response to histamine and gastrin 
and inability of the mucosa to secrete neutral red. True 
achylia gastrica is a rare condition. Either condition may 
be found in pernicious anemia, usually achlorhydria. The 
distinction between the two is one of degree of failure of 
the gastric secretory function. The former is an instance 
of relative, the latter the instance of complete, delinquency 
of physiological activity. 

There exists a tendency to dismiss the subject of 
achlorhydria with an unjustified assumption that the con- 
dition is due to the absence of an unrecognized hormone, 
or to suppose that it is part and parcel of a metabolic dis- 
turbance of some substance such as, for example, the 
chlorides. What has physiology to offer in explanation of 
this phenomenon ? 

Present conceptions of the physiology of gastric secre- 
tion are based on the work of Pavlov (488), Edkins, 


ETIOLOGY ct 


Carlson, Ivy, and others. Ivy (317) would divide stomach 
digestion into three phases. (1) The cephalic stage, 
which corresponds to the psychic stage of Pavlov but 
includes the operation of lower brain centres than the cor- 
tical. (2) The gastric phase, which includes the mechan- 
ical and chemical influence of food on the stomach. (3) 
The intestinal phase, during which gastric secretion is 
aroused by contact of HCl, digested foods, soaps, and 
other substances with the duodenal mucosa. Edkin’s work 
on gastrin sounds the key-note to present investigations 
which are largely concerned with establishing a humoral 
mechanism. Edkin’s gastrin was extracted from pyloric 
mucosa by weak acid, peptone, or partly digested protein 
solutions. Similar substances may be extracted from many 
tissues. That from hog’s stomach and duodenum was 
shown by Ivy and Fisher (319) to resemble insulin in its 
lowering of blood sugar, while insulin, on the other hand, 
does not stimulate gastric secretion. Rogers et al. (532) 
made extracts from various organs, administered them 
subcutaneously and found those from thyroid, parathy- 
roid, liver, and pancreas definitely stimulated gastric 
secretion, while others did not. But these extracts showed 
other physiological activities, as depressors and as 
smooth-muscle excitants, each with effects peculiar to 
itself. They felt unjustified in assuming the existence of 
any specific hormone acting only on the stomach, although 
a common element in their various extracts seemed to act 
as such. In Ivy, Lim, and McCarthy’s (320) cross-circu- 
lation experiment between two Pavlov pouch dogs, by 
feeding the one and noting the gastric secretion in the 
other, a definite suggestion was obtained of a circulating 
gastric stimulant, appearing late in digestion. Ivy and 
Farrell (318) were next successful in transplanting a 
stomach pouch into the mammary tissues of a female dog 
and in showing that in this miniature stomach, separated 
as it was from nerve supply, there appeared an acid 


52 PERNICIOUS ANEMIA 


secretion at a period some hours after a meal. This fur- 
nishes incontestible evidence of the operation of a humoral 
mechanism, depending probably on circulating food sub- 
stances. The secretion of gastric juice is therefore a phy- 
siological activity for the production of which nervous, 
mechanical, and humoral factors have been established, 
but for which no definite hormone had been found. 

The clinical and pathological studies of human gastric 
disease teaches the one great lesson that the stomach is a 
barometer indicating the general condition of well-being 
or cachexia. Carlson (101) believes that the hypoacidity 
of pellagra and beri-beri is an expression of the cachexia 
of diet deficiency. Achlorhydria is frequently found in 
the toxemias of pregnancy and is always present, so far 
as critically reported, in the chronic hemolytic anemia of 
pregnancy which bears so close a resemblance to perni- 
cious anemia. Faber has shown that of all the cases of 
dibothriocephalus latus infection which develop the per- 
nicious-like anemia, only twenty-five per cent have normal 
gastric acidity, many of them showing achlorhydria. 
Achlorhydria is liable to be found associated quite fre- 
quently with the following conditions—exophthalmic 
goitre, arthritis deformans, cholecystitis, and appendicitis. 
As will presently be emphasized it may occur, and in fact 
usually does occur, without association with any disease. 
Faber and Gram (188) have made a definite recognition 
of a severe, simple anemia, with low color index, red 
corpuscles smaller than normal, fluctuant in character and 
temporarily relieved by iron, which may accompany 
achlorhydria whether the achlorhydria is uncomplicated 
or is complicated by exophthalmic goitre or arthritis 
deformans. 

Achlorhydria has not been produced experimentally by 
any purely physiological means. When produced by in- 
toxications or by prolonged drainage of a gastric fistula, 


ETIOLOGY 53 


it does not appear until the general cachexia would seem 
to demand it. 

Not only are we in ignorance of the cause of achlo- 
rhydria, but we are equally in ignorance, so far as accur- 
ate knowledge is concerned, of its consequence. 

Such symptoms as anorexia, persistent painless regur- 
gitation, feelings of distension, and chronic recurring 
diarrhoea, might be attributed to achlorhydria except that 
achlorhydria so commonly exists without them. Achlor- 
hydria apparently results in disturbances of the intestinal 
flora of equal degree whether in pernicious anemia or in 
uncomplicated cases. These changes in the intestinal flora 
will be considered later. From the fact that free HCl has 
been recognized as an essential intermediary in the stimu- 
lation of the pancreatic juice, it might be expected that a 
condition of achylia pancreatica would result. The inves- 
tigations of Hurst (307) and of McClure et al. (414) 
indicate, however, that the pancreatic function is normal 
both as regards enzyme secretion and alkaline fluid 
secretion. Achlorhydria exerts a definite influence on the 
acid-base balance of the blood, as proved by the numerous 
investigations, from Schittenhelm to Ackman, of the 
phenomenon of the “alkaline tide” of the urine (41, 99, 
102126; V5), 202) 214,232, 234,257, 282, 283, 262, 355, 
384, 402, 407, 515, 516, 556). The degree of alkaline tide 
varies directly with the degree of acidity in the stomach, 
being absent or diminished in cases of achlorhydria and 
completely absent in cases of true achylia gastrica. 

Whatever its causes or consequences may be, achlo- 
rhydria is almost invariably associated with pernicious 
anemia. 

The converse of this statement, however, is not true. 
Achlorhydria may exist, and usually does exist, without 
pernicious anemia. Bennett and Ryle (42) found achlo- 
rhydria in four per cent of one hundred medical students 
of an average age of twenty years. Wright (667) found 


54 PERNICIOUS ANEMIA 


achlorhydria in 1.6 per cent of two hundred and fifty 
children between the ages of six and fifteen years. Faber 
(188) estimated that of all achlorhydric individuals ten 
per cent develop pernicious anemia. Among the other 
ninety per cent some may suffer from comparatively less 
fatal diseases—exophthalmic goitre, arthritis deformans, 
appendicitis, cholecystitis—although the majority remain 
in good health. 

It would seem advisable to adopt the following tenta- 
tive conclusion: Achlorhydria, a functional abnormality 
of constitutional origin, is almost invariably associated 
with pernicious anemia, and forms in these cases a neces- 
sary link in an etiological chain, to which, by the addition 
of further unknown links, pernicious anemia is made to 
appear. 

Nerve tissue degeneration. Since Lichtenstern (373) 
reported posterior column degeneration associated with 
pernicious anemia in two cases diagnosed as tabes, but 
which were probably cryptogenic pernicious anemia, the 
subsequent studies of Lichtheim (374), Putnam (504), 
Dana (137), von Noorden (624), Eisenlohr (168), Min- 
nich (437), Russell, Batten, and Collier (543), and many 
others have established the occurrence of combined system 
degeneration in association with pernicious anemia. Since 
1910 the combined work of the Déjerines, Crouzon, and 
Jumentie (140, 141, 142), of Cadwalader (93), Schaller 
(550), and others has resulted in better understanding 
of the nervous system signs and symptoms. Woltman 
(662) has demonstrated the occurrence of brain lesions 
similar to those in the spinal cord. Hamilton and Nixon 
(253) have studied the sensory phenomena in particular 
and made the important observation of the commonness 
of peripheral nerve degeneration. 

Pathologically, the nervous system in a well-developed 
case shows wide changes. Posterior and lateral column 
degeneration, in varying proportion, definite cerebral 


ETIOLOGY 55 


degeneration running more or less parallel to the degree 
of cord involvement, and widespread peripheral nerve 
degeneration constitute the phenomena. These degenera- 
tions occur in the myelin sheaths of long nerves and long 
tracts, being stained by Wiegert’s method, and have sug- 
gested to Woltman the operation of a toxin. Collier (124) 
has noted the absence of neurogliar increase following 
these lesions, a fact which gives them a unique position 
in nervous generations. Piney (500), noting this, has 
viewed the alterations as illustrations of abiotrophy. 

During remissions of the disease no improvement 
occurs in objective nervous signs, although the process 
frequently becomes quiescent. The disharmony noted 
between symptoms and pathological cord findings is to be 
explained, according to Hamilton and Nixon (253), on 
the basis of the peripheral nerve degenerations. Blanken- 
horn (48) has suggested that bile salts in the blood might 
be seriously considered as the cause of the nervous degen- 
erations, since bile salts may be found in the blood in 
cases showing definite nervous involvement but compar- 
atively little anemia. 

The obtrusive sensory symptoms of numbness and 
paresthesia may constitute the first indications of the 
disease. Marked objective signs may develop rapidly 
without anemia, or more slowly without anemia and con- 
tinue for years in a chronic course without anemia until 
terminally, when the specific type of anemia develops. 
The commonest type of case is one in which the nervous 
manifestations begin, some months after the onset of the 
anemia, with weakness. In later stages of pernicious 
anemia the true state of the patient is more related to 
nervous changes than blood changes. A patient may die 
with a fair blood level maintained. The presence of nerve 
changes always indicates a more severe phase of the dis- 
ease than when blood changes are alone present. 


56 PERNICIOUS ANEMIA 


While this type of cord change—combined system 
degeneration—occurs much more commonly in pernicious 
anemia than in all other conditions combined, it is not to 
be forgotten that very similar changes may be found in 
poisoning with lead, arsenic, ergot, chick-peas, alcohol 
(chronic), and tea; and in shock, pellagra, diabetes, 
leukemia, diphtheria, Addison’s disease, tuberculosis, 
syphilis, typhoid, carcinoma, senility, chronic jaundice, 
malaria, influenza, scarlet fever, tetanus, and pregnancy. 

The fatty changes. These affect chiefly the heart and, 
in most cases, the liver and kidneys as well. These familiar 
facts must be merely stated because of their probably 
specific relationship to the fundamental process of the 
disease, although their nature is obscure. 

The remissions. A remission is a spontaneous blood im- 
provement characterized by general symptomatic im- 
provement. Panton et al. (482) found that 85 per cent of 
cases showed remissions and 15 per cent did not. The re- 
missions are subject to no known laws with regard either 
to their rapidity of onset, their duration, or their excel- 
lence, in any given case. The excellence of a remission 
may be judged by its duration, the degree of strength re- 
gained, the degree of blood regeneration, and the degree 
of disappearance of morphological abnormality on the 
part of the blood corpuscles. The objective nervous signs 
do not improve, although nervous involvement does not 
often increase during remissions. Glossitis frequently 
continues during all but the most excellent remissions. 

A remission is probably a period of comparative free- 
dom from the operation of the causal process, rather than 
a period of bodily reactive improvement in the face of 
continued disease. Nevertheless, the recoverability of all 
tissues which can recover may be seen to be less and less 
with each subsequent remission, for, although exceptions 
occur, there is to be noted a downward gradient when the 
remissions in any one case are compared. 


ETIOLOGY o/ 


While the health of the patient, in the earlier stage of 
the disease, may be said to follow roughly the hemoglobin 
level, there occurs a definite disruption of this relation- 
ship later on, for patients may die while their blood re- 
mains at a comparatively satisfactory level. In the later 
stages the true condition of the patient is better expressed 
in terms of the nervous system involvement. 

If our conception of the cause of the disease is that of 
an active destructive agent, then a remission would ra- 
tionally be regarded as a period during which this agent 
was either absent or in comparative abeyance. If our con- 
ception of the cause of the disease is that of a deficiency 
of certain factors vital to metabolism, then a remission 
would rationally be regarded as a period during which 
these factors are replaced. In either case a fluctuating 
mechanism is apparent. Furthermore, it is to be observed 
that whereas the blood system and nervous system are 
affected by remissions, the former positively and the 
latter negatively, the digestive system retains at least 
one unaffected principle—the achlorhydria. 

The general metabolism. Omitting references for the 
sake of brevity, the following points are selected from 
the mass of somewhat discordant findings. There is no 
evidence of any abnormality of carbohydrate metabolism. 
So far as lipoids are concerned, there is a recognized de- 
pletion of blood cholesterol during severe phases of the 
anemia, and usually a high ratio of unsaturated fatty 
acids in the blood though not to a distinctly pathological 
degree, a satisfactory usage of fat eaten, and no evidence 
of abnormal metabolism of simple fats, although there is 
a tendency to over-storage of fat, and a tendency also, to 
the pathological infiltration by fat in active tissues. Con- 
cerning protein metabolism, there is a tendency to a nega- 
tive nitrogen balance; amino-acids are increased in the 
blood and the urine shows double the normal amount of 
oxyproteic-acid nitrogen. Blood creatinin is increased. In 


58 PERNICIOUS ANEMIA 


this connection the extreme muscular wasting, especially 
in cases of marked cord involvement, should be borne in 
mind. Any increased protein catabolism is probably an 
expression of the cachexia, as in that of carcinoma and 
syphilis. The usually high uric acid nitrogen suggests that 
the purine metabolism requires further study, especially 
in view of the benefits derived from feeding with glandu- 
lar organs. The metabolism of iron has already been dis- 
cussed. There exists a tendency to chloride retention al- 
though there is no evidence that an abnormality of 
chloride metabolism plays an important role in the dis- 
ease. Studies of the basal metabolic rate have served to 
suggest that the use of energy is determined by two oppos- 
ing factors, (1) a positive stimulation connected probably 
with increased blood production, (2) a retarding influ- 
ence due to the tendency to storage and infiltration of fat. 


ETIOLOGICAL EVALUATION OF OTHER POSSIBLE 
RELATED FACTORS 


The type or constitutionality of the patients. This prob- 
lem involves a description of certain alleged constitutional 
factors common to these patients and some reference to 
familial pernicious anemia. Addison (5) noted that the 
disease occurred “‘chiefly in persons of a somewhat large 
and bulky frame.’ While this is often true, it may also 
occur in small, lean persons. Maitland-Jones (394) as 
well as Levine and Ladd, have noted the great frequency 
of gray or white hair. Sheard (576) among 15 cases 
found but one exception to this apparent rule. In the 14 
cases showing the feature, he determined that the aver- 
age age at which grayness commenced was 29.4, which 
was 15 years prior to the average age of the onset of the 
disease. He further noted, as others have, the frequency 
of “silky” or very fine, soft hair. 

Achlorhydria is of course the most striking feature of 
the disease which could be interpreted as a constitutional 


ETIOLOGY 59 


one. Bassler and Gutman (31), in studying the constitu- 
tionality of achlorhydric individuals, have placed them 
in the “adrenotrope” group—females of the masculine 
build, males of the apoplectic diathesis, with tendency to 
pigmentations, very firm and stained teeth, and great 
mental susceptibility to external influence. 
Anthropological measurements of a most painstaking 
character have been made by Draper (153) on 45 cases 
of pernicious anemia. For a full understanding of his 
motives and methods reference should be made to his 
book. As compared with similar measurements in other 
disease groups (gall-bladder, gastric and duodenal ulcer, 
asthma, nephritis and hypertension, and pulmonary tu- 
berculosis), Draper found as follows :—people with per- 
nicious anemia have short broad faces; large mandibular 
angles; very short noses; short but deep, wide chests; 
especially wide subcostal angles; and (especially the 
males) very long thin ears. “The male of the pernicious 
anemia race, therefore, is a medium to tall individual with 
short chest, high placed umbilicus, long abdomen, and a 
tendency to eunuchoidal habitus as shown by his rela- 
tively long lower extremities. The males of this group 
show definite feministic tendencies in the domain of the 
secondary sex characteristics. But the skeletons show 
average or greater sex divergence in the growth of the 
long bones. In this case the convergence of sex insignia 
upon the so-called intermediate form is more marked than 
in any other disease group. This may be reflected in the 
wider pelvis of the male of the pernicious anemia group. 
In commenting upon Draper’s work, Stockard (598) says 
in part, “The pernicious anemia group tended in their 
measurements very decidedly to approach the acrome- 
galics. They had very large subcostal angles and had an 
average profile that tended toward the acromegalic pic- 
ture. The anemic persons may by some possibility be a 
peculiar deviation from the bone growth stage of the 


60 PERNICIOUS ANEMIA 


acromegalics. Both conditions may have some connection 
with calcium metabolism, and blood disturbance and bone 
disturbance in this way may be somehow interrelated.” 

Stockard favors the view that type differences are evi- 
denced by marked variation in anatomical measurements 
but that constitutional differences may exist in members 
of the same type and be due to such influence as the en- 
docrine glands, so that while type is permanent, consti- 
tutionality may vary, even in an individual. Further work 
by Draper, especially on the physiological, psychological, 
and immunological aspects of the members of these dis- 
ease groups, will be awaited with interest. A possible re- 
sult of such investigations may be the division of people 
into species or subspecies. 

Sufficient has been written to indicate that there exists 
some reason why investigators and writers on pernicious 
anemia should suspect that these patients may possess at 
lease a definite peculiarity of constitution if not of type. 

Minot (444) informs the writer that Palmer Howard 
was first to note the familial occurrence of pernicious 
anemia. Klein (340) in 1891 saw the disease in three 
brothers and sisters. Bramwell a little later described a 
family in which seven individuals in two generations had 
suffered from pernicious anemia. Since then the phenom- 
enon has been noted by Caccini (92), Schauman (551, 
554), Bulland (241), Cabot (90), Osler (477), Gilbert 
and Weil (225), Patek (486), Willson (658), Andree 
(12), Bartlett (29), Roth (538), Minot (440), Piney 
(449), Matthes (409), and others. Schauman by 1918 
had collected information of 24 families in which there 
was noted hereditary occurrence of either idiopathic per- 
nicious anemia, or the pernicious-like anemia due to 
bothriocephalus, or both of these, in the same family. 
More recent confirmation of familial occurrence has come 
from the reports of Levine and Ladd (370), Meulen- 
gracht (430), Gram (218), v. Decastello (623), Muste- 


ETIOLOGY 61 


lin (466) and Gilford (226). Meulengracht (433) has 
considered the technicalities involved in an hereditary 
study of pernicious anemia. Hurst has collected many in- 
stances in which achlorhydria has been found among the 
blood relatives of patients with the disease, strongly sug- 
gesting that the obvious link in the chain is absence of 
gastric secretion. Piney (500) distinguishes between me- 
galoblasts with reticular nuclei and those with “cart- 
wheel” nuclei, and contends that the former or true vari- 
ety are found only (apart from the embryo) in perni- 
cious anemia and acholuric family icterus, the two “dis- 
eases of the blood” in which family incidence is well recog- 
nized. He noted in his own cases a frequent history of the 
patient not having been a full term infant. Piney believes 
that the abnormal type of blood formation in pernicious 
anemia is an embryonic reversion, due to inherited pro- 
pensities of the individual, and possibly related to the 
constitutional achlorhydria. The nervous tissue degenera- 
tions he would interpret as an abiotrophy. Finally he sug- 
gests the working hypothesis, with which all cannot of 
course agree, that the various agents capable of produc- 
ing a “secondary” anemia in ordinary persons will pro- 
duce pernicious anemia in such individuals as possess 
the necessary remnant of megaloblastic tissue. This is 
practically Cohnheim’s hypothesis reinforced by distinc- 
tions between two alleged types of megabloblasts and by 
observations on the family incidence. Barker (24) has 
recently considered the hereditary factors and stated the 
possibility of the view that pernicious anemia is a geno- 
typic disease, possible only in biotypes, but requiring for 
its development certain “releasing factors” in the envi- 
ronment. He comments upon the difficulties of applying 
the method of statistical summation and offers three rea- 
sons why the disease may be absent in families where it 
might be expected to occur under the inheritance theory. 
(1) It is a disease of later life, many potential candidates 


62 PERNICIOUS ANEMIA 


dying before it can become manifest. (2) Many cases are 
overlooked. (3) The possibility that the “releasing 
factors” have not been operative upon these individuals. 

The genotypic conception of pernicious anemia is at 
present of little more than academic interest and whether 
it eventually proves convincing or otherwise, ordinary 
studies must be pursued to determine the sequence of 
events in the pathogenesis. 

The food factor. The voluminous work on vitamins dur- 
ing the past decade unquestionably suggested that avita- 
minosis might play some role in pernicious anemia. Fal- 
coner concluded that blood changes in vitamine A defi- 
ciency were neither striking or constant enough to consti- 
tute specific deficiency lesions. Koessler et al. (346) do 
not indicate the condition of pigment metabolism in the 
anemia they produced in rats by chronic vitamine A 
deficiency and, hence, any comparison with pernicious 
anemia, lacking this information, is problematical. They 
indicate that in this experimental anemia, produced by 
vitamine A deficiency, blood regeneration occurs only 
with, and in proportion to, the addition of vitamine A. 
Nothing could appear more logical, since no anemia can 
improve so long as the set of conditions responsible for 
the anemia do not change. Simmonds e¢ al. (579) sug- 
gest that Koessler’s rat anemia was due to deficiency in 
vitamine E, which is believed to play an important role 
in the absorption of iron. Whatever may have caused the 
anemia, it does not, from their description, appear to bear 
any necessary relationship to pernicious anemia; and in 
fact Koessler et al. propose such a vitamine A deficiency 
not as a sole, but rather as a cooperative factor in the 
etiology of the human disease. 

Barker and Sprunt (25) emphasized the importance, 
on general principles, of treating pernicious anemia by 
liberal and well-balanced diets. Many others have, with 
no recognizable specific reason of importance, advised 


ETIOLOGY 63 


special diets of various kinds. Mosenthal (454) showed 
that forced feeding can restore a positive nitrogen bal- 
ance. Gibson and Howard (223) showed in careful meta- 
bolic experiments, that more favorable nitrogen and es- 
pecially iron balances may be established in pernicious 
anemia when diets rich in food iron, and comparatively 
low in caloric and protein values are given, and urged 
the use of iron-rich and vitamine adequate diets in the 
treatment of this disease. This was an intentional, clinical 
application of high food iron diets which had been found 
by Whipple ez al. (648, 652, 651) so valuable in causing 
blood regeneration in dogs rendered anemic by hemor- 
rhage. Elders (169), fully convinced of the possibility 
that sprue and pernicious anemia possess a common etio- 
logy, and equally convinced that sprue is a deficiency dis- 
ease, suggested that pernicious anemia might be found 
at least amenable to improvement by well-chosen food. 
Minot and Murphy (447) found it permissible to specu- 
late “on the possible partial role that some nutritional ex- 
cess or deficiency may play in the etiology of the disease.” 
With a special diet rich in proteins of good biological 
value, particularly liver, low in fat and carbohydrate and 
with vitamines well supplied, these investigators have 
obtained remarkable therapeutic results, more constant 
and lasting than those obtained by any other form or 
forms of treatment. The published work of Minot and 
Murphy has brought the whole problem of nutrition 
in pernicious anemia to a sharp focus of interest. Their 
results have suggested the possibility that dietary factors 
may actually play a role in the production of the disease. 
No studies of the pre-disease diets of patients have as 
yet appeared. 
SIMILAR CLINICAL ANEMIAS 

Waugh (637) in his classification of anemias would 
regard pernicious anemia as the idiopathic member of a 
limited group designated as “hyperchromic hemomyelo- 


64 PERNICIOUS ANEMIA 


toxic anemias.” This group includes the chronic hemolytic 
anemia of pregnancy, dibothriocephalus anemia, some 
cases of gastric cancer, some cases of sprue, and others 
which will be mentioned. 

The common expression “pernicious blood-picture” is 
a loose unstandardized term, the meaning of which varies 
according to the views of the person using it. It is some- 
times erroneously used to describe a frankly aplastic 
anemia in which evidence of pigment disturbance does 
not appear. Disturbance of pigment metabolism is of 
primary importance. But there are several anemias whose 
hematological data as a whole suggests pernicious anemia. 
Such are encountered in a few each of the following con- 
ditions :—carcinoma of the stomach, syphilis, pregnancy, 
dibothriocephalus infection, sprue, colonic cancer, balan- 
tidium coli infection, aleukemic leukemia, malignant 
metastases to the bone marrow, and as Minot (442) as 
well as Meulengracht has pointed out, in a very occa- 
sional case of myxedema. These instances, however, 
judged even by purely microscopic evidences in the blood 
smear, seldom fulfill the requirements of pernicious 
anemia. The crucial test is the predominance of macro- 
cytes, heavily staining, and exhibiting in at least 80 per 
cent of their number definite ovality of outline. It is there- 
fore possible by rigorous microscopic standards to ex- 
clude most of these instances. All standards we possess 
are nevertheless very occasionally defeated by cancer of 
the stomach, sprue, and fish-tapeworm infection. Needless 
to remark, even such blood identities as these sometimes 
are do not justify their designation as pernicious anemia. 
But when, in addition to blood identity, there appear in 
such cases the additional features of glossitis, achlorhy- 
dria, and combined degeneration of the cord, escape from 
the dilemma is found by making a double diagnosis. Such 
a dilemma may actually be encountered in gastric and 
colonic cancer, and in sprue. 


ETIOLOGY 65 


There is little doubt that carcinoma of the stomach and 
of the colon may at times produce a macrocytic anemia 
in which the macrocytes are circular rather than oval 
and exhibit a degree of achromia never seen in perni- 
cious anemia. It is also true that sprue not infrequently 
produces a severe anemia with marked anisocytosis, but 
this is not pernicious anemia but merely the anemia of 
sprue. Furthermore, a few cases of dibothriocephalus 
anemia show such a striking identity with that of perni- 
cious anemia that distinction rests on associated signs or 
the discovery of the worm. The etiological value of such 
resemblances is to demonstrate that various known condi- 
tions can cause very similar anemias, a fact which puts 
us on guard in interpreting experimental blood-pictures 
and which indicates, too, that a so-called ‘pernicious 
blood-picture” is not a strictly specific phenomenon. 

In instances where the whole Addisonian complex su- 
pervenes in a known disease, we are driven to choose be- 
tween accidental occurrence or causal relationship. It is 
not impossible that sprue, gastric cancer, and dibothiro- 
cephalus infections possess at times a common meeting 
ground with pernicious anemia, in the form of a funda- 
mental process which, once brought into being, is identi- 
cal in its operation and consequence. 


A REVIEW OF EXPERIMENTAL FINDINGS 


Since most of the experimental work on this disease 
has been dominated by the conception that it is caused 
by a blood-destroying agent, absorbed from the gastro- 
intestinal tract, it is necessary to define the so-called 
“hemolytic theory” and to consider also the general prob- 
lem of poisoning from the intestine. 

The requirements of any hypothetical tox. It is clear- 
ly to be understood that no definite proof of a toxin exists. 
The absence of in-vitro hemolysis by patient’s serum may 
be made congruous with a toxin theory by supposing that 


66 PERNICIOUS ANEMIA 


the toxin, wherever produced, is immediately absorbed to 
the erythrocytes, or is removed from the circulation by 
the reticulo-endothelial system, the latter being thus ren- 
dered inimical to the red blood cells. Extracts of the 
spleen in this disease are not hemolytic. Really the chief 
reason for hypothesizing a toxin is that in bothriocepha- 
lus anemia the cause is supposed to be the autolysis pro- 
ducts of the worm operative through absorption by the 
intestine. This is not a very logical reason since no one has 
shown that the truly hemolytic products are absorbable 
from the human intestine. 

If a toxin be hypothesized, then unity of toxin is sug- 
gested by the strikingly similar clinical and pathological 
pictures in all cases. Plurality of toxins finds its best 
argument in the occurrence of subacute degeneration of 
the cord temporarily without anemia, and perhaps in the 
occurrence of splenomegaly in certain cases. The differ- 
ence between the so-called “hemolytic” and ‘“myelotoxic” 
cases might better be called a difference in “activity” and 
would then depend on the dose of toxin delivered to the 
body. 

If a toxin causes this disease per se, by direct action 
on the tissues pathologically implicated, and without the 
necessary intermediate codperation of any vital function, 
it must possess both hemotoxic and neurotoxic powers. 
To account for remissions the toxin must possess immu- 
nological properties or be produced by a fluctuant mech- 
anism, or both. 

Any toxin must be shown to be specifically active with- 
in the body. Its lack of hemolytic activity in the test tube 
would not disqualify it. 

Any toxin to be seriously considered would have to 
produce: (1) A megaloblastic marrow reaction, (2) a 
characteristic blood-picture, (3) nerve tissue degenera- 
tion without neurogliar increase, (4) remissions either by 
intermitting doses or in spite of constant dosing. 


ETIOLOGY 67 


No such toxin has been demonstrated. 

Gastro-intestinal toxemia. Although Hunter’s (297) 
own investigations of various intestinal poisons did not 
support this conception he clung to it for several reasons. 
The marked symptomatology of the digestive tract was 
one. A still more convincing one was his interpretation 
of the hemosiderin deposits. Having demonstrated this 
iron pigment in the liver in higher concentration than in 
the livers of other anemias, and having accepted hemo- 
lysis as responsible, he (290) assumed that the hemolysis 
took place largely within the portal area. 

Since 1885 the intestinal toxemia theory has held its 
own with special investigators and particularly with the 
rank and file of general practitioners. It has many rami- 
fications and although it merges with the trite and com- 
mon idea of intestinal “auto-intoxication” so glibly ac- 
credited with all manner of ailments, any thesis so long 
sustained deserves consideration. 

Intestinal intoxication has received a very excellent 
general evaluation from Alvarez (8). The greatest objec- 
tions to the idea are the tremendous number of poisons in 
the lumen of the bowel and lack of knowledge of their 
individual absorbability by the mucosa. Much investiga- 
tion of individual poisons has led in almost no instance 
to any proof of their absorption in harmful amounts into 
the general circulation. The toxin of B. botulinus is per- 
haps an exception. Intoxication from high obstruction 
admits the element of a pathological state of the mucosa. 
The absorptive faculties of this tissue in health would 
appear to be uniformly very selective ones. As a second 
barrier to the ingress of harmful substances stands the 
liver with its detoxicating functions. Any specific hypo- 
thesis of intoxication from the gut would require to show 
at the outset that the suspected substance could pass into 
the general circulation in a harmful state. The only alter- 
native to this requirement would be a demonstration of 


68 PERNICIOUS ANEMIA 


increased absorption by the mucosa in pernicious anemia. 
Such a theory has been advanced by Koessler et al. (346) 
as one of the fundamental changes in the disease. If this 
were successfully shown to be true, intestinal intoxication 
would at once assume greater seriousness. 

The only actual work in connection with pernicious 
anemia which might lend support to the theory of intes- 
tinal intoxication was that of Iwao (321), who reported 
that tyramine injections in guinea pigs produced a se- 
vere anemia of “pernicious” type. Since tyramine can be 
formed from tyrosine by B. coli and is therefore normally 
present in the bowel, this work looked promising, but 
Koessler and Harris failed to confirm it. 

The gastro-intestinal mucosa itself, either alone or in 
association with abnormal states, has been viewed with 
suspicion. About a dozen cases have been reported in the 
literature in which pernicious anemia was associated with 
chronic intestinal stenosis. Seyderhelm (573) produced a 
“macrocytic” anemia in dogs by stenosing the small in- 
testine near the ileo-caecal valve. In such dogs, and in 
cases of pernicious anemia, Seyderhelm has noted an en- 
croachment on the ileum of the colonic flora. Haden’s 
(247) case of clinical and hematological pernicious ane- 
mia associated with malignant tumor of the gall bladder 
and partial obstruction of the duodenum and colon, sug- 
gested to him the absorption of toxin, and an analogy with 
the toxemia of complete intestinal obstruction. 

Apart from obstruction or any gross lesion involving 
the digestive tube, the mucosa itself has long been sus- 
pected. Berger and Tsuchiya (43) in 1909 found in the 
intestinal mucosa in two autopsies an ether soluble sub- 
stance ten times more hemolytic im vitro than a similar 
extract from normal musoca. On enteral or parenteral in- 
troduction into animals it was still more hemolytic than 
its control and produced an anemia bearing some resem- 
blance to that of pernicious anemia. This work was not 


ETIOLOGY: 69 


confirmed (78). Dogs in whom a severe intestinal catarrh 
was artificially produced showed in their mucosa a lipoidal 
substance closely resembling in its action that found 
in the mucosa in pernicious anemia. Cornell (133) noted, 
during an attempt to implant B. welchii in the intestine 
of dogs, an initial severe diarrhoea accompanied by an 
evanescent mild anemia with definite anisocytosis. How- 
ard (278) stressed this aspect of the study of toxic lipoids 
from the intestinal mucosa. The question deserves some 
further study. Briefly, while there is every reason to sus- 
pect the gastro-intestinal tract, there is absolutely no 
reason positively to incriminate it of giving rise by any 
means whatsoever to a poison responsible for the disease. 

The intestinal flora. Every organism that inhabits the 
lumen of the gut in pernicious anemia has been suspected 
of causing the disease. The enterococcus is increased in 
the stools and lives higher in the duodenum than in health 
or other disease. This is also true of B. coli. B. welchii is 
increased in the stools but no work has been published to 
indicate whether or not it lives higher in the duodenum. 
Streptococcus longus has been reported abnormally pres- 
ent in the duodenum in a high percentage of cases. From 
all the investigations made, two facts are significant. A 
good case has not been made out against any organism, 
and no exceptional one specific to the disease has been 
found. 

The B. welch theory. This micro-organism (B. 
aerogenes capsulatus, B. perfringens) is an anerobic, 
program-positive, encapsulated bacillus which spores 
with difficulty on artificial media. When living cultures 
are injected into the ear veins of a rabbit and the rabbit 
killed and incubated, a “foamy” liver develops. The or- 
ganism has been divided into four groups by Simmonds 
on the basis of its power to liquify gelatine. It was first 
identified by Welch in a case presenting gas in the tis- 
sues at autopsy. It was later shown, especially in the 


70 PERNICIOUS ANEMIA 


great war, to be a constant factor in the production of 
gas gangrene. Bull and Prichett (80) demonstrated a 
soluble exotoxin possessing distinct hemotoxic and lethal 
elements. This toxin is thermolabile and has immunolo- 
gical properties. The antitoxin from the horse or rabbit 
neutralizes in vitro the hemotoxic and lethal elements 
and cures the symptoms of an acute experimental infec- 
tion in guinea pigs, if promptly administered. 

A possible relationship between this organism and per- 
nicious anemia was first suggested by Herter (268) in 
1906. He found B. welchii or its spores numerically in- 
creased in the stools of this disease as compared with the 
stools from normal or other diseased conditions. Sim- 
monds (578) later confirmed this finding. Although he 
was working at a time before the exotoxin was known, 
Herter felt that the stools showed altered chemical fea- 
tures due to this organism. He very tentatively suggested 
that B. welchii might be the cause of the disease, evidently 
meaning that in causing it, it led a life confined to the 
lumen of the intestines, while its harmful growth pro- 
ducts were absorbed into the circulation. His hypothesis 
therefore must be interpreted as a specific application of 
the intestinal intoxication idea, for he made no sugges- 
tion of tissue invasion by this organism. 

Cornell (134) showed that B. welchii caused a chronic 
infection when injected subcutaneously or intraspleni- 
cally into rabbits. This infection ran a course of a few 
months and was characterized, among other symptoms, 
by an anemia of varying intensity, the constant feature of 
which was anisocytosis. This anisocytosis was due to a 
direct action of the exotoxin on the erythrocytes and oc- 
curred in vitro in washed cells. The smear picture bore 
no little resemblance to that of pernicious anemia, but the 
macrocytes were characteristically circular rather than 
oval, the microcytes appeared like contracted rather than 
fragmented cells, and neither blood platelets nor leuko- 
cytes were depressed sufficiently. 


ETIOLOGY 71 


Kahn and Torrey (332), working at the same time on 
the effect of intravenous injection of the toxin in mon- 
keys, obtained very similar blood pictures, but with high- 
er color indices and more leukocyte depression. Reed, 
Orr, and Burleigh (518) showed that a highly virulent 
strain of B. welchii would produce an infectious anemia 
in rabbits whose acuteness or chronicity depended on 
the age of the culture used but that, in any case, anisocy- 
tosis was conspicuous and resembled quantitatively that 
of pernicious anemia. 

Moench, Kahn, and Torrey (448) in an analysis of the 
fecal flora in 35 cases of pernicious anemia showed that 
B. welchii gives uniformly higher counts than normal, 
that among 26 different strains isolated 50 per cent con- 
formed to Simond’s Type I, but that none could be shown 
to be more hemolytic or pathogenic than strains from 
normal stools. They consider that if B. welchii is to be 
brought into etiological relationship with pernicious ane- 
mia it must be because of its increased numbers and ac- 
tivity at a level of the tract higher than ordinary, where 
absorption is more active. They support Seyderhelm’s 
(572) observation of the invasion of the ileum by the 
colonic flora and consider this to be of importance. 

Nye (475) showed that an equal or even greater in- 
crease of B. welchii could be demonstrated in the feces of 
cases of uncomplicated achlorhydria. He feels that the 
phenomenon depends on an alkaline condition of the prox- 
imal ileum and is therefore merely a consequence of 
achlorhydria and not an etiological factor in the disease. 

A bacterial study of the stools at Guy’s Hospital (180) 
does not seem to have confirmed the invariable presence 
of B. welchii in increased numbers. 

There is no convincing evidence to support this hypo- 
thesis. The toxin has neurotoxic properties but the chronic 
infection in rabbits showed no combined system dis- 
ease, no alterations in gastric secretion, and no remis- 


72 PERNICIOUS ANEMIA 


sions. The toxin has never been shown capable of ab- 
sorption from the intestine. In fact it is questionable if 
the organism living in the gut could produce a toxin com- 
parable with that produced under very special culture 
conditions. It probably cannot be regularly found in the 
internal organs after death and its presence might al- 
ways be due to agonal invasion. In some animals this or- 
ganism may be cultured from the liver during life and 
health. No agglutination or complement fixation by the 
serum on the organism or its toxin has been found, al- 
though both have been looked for. The blood picture pro- 
duced by the chronic infection or by the continued injec- 
tion of toxin, while definitely suggestive, is really not the 
blood picture of pernicious anemia and may best be classi- 
fied as a toxic, macrocytic, hemolytic anemia. Finally B. 
welchii antitoxin has been repeatedly administered to 
patients without visible benefit. 

The streptococcus theory. Hunter (303) made micro- 
photographs of the glossitic lesions showing a long strep- 
tococcus in the subepithelial layer of the tongue at those 
eroded areas where the mucosa was gone. From such les- 
ions he claims to have obtained this organism in a highly 
virulent state in pure culture. To this organism he attri- 
buted largely the septic manifestations which so fre- 
quently accompany or antedate the true specific anemia, 
but he never incriminated it as the cause of the latter. 
Hemolytic streptococci have been found in the gall blad- 
der in cases of cholecystitis associated with pernicious 
anemia. Knott (345) found, as did Hunter, large num- 
bers of living streptococcus longus in the gastric contents 
of patients and in increased numbers in the saliva. Ryle 
(544) sets forth, as characteristic of a streptococcus 
fever, a rapidly progressive anemia, a curiously smooth, 
red, desquamated tongue, both of which features are 
caused by a circulating cytolytic toxin. Newburg (470) 
has reported a case of pernicious anemia in which a hem- 


ETIOLOGY 7s 


olytic streptococcus was cultured from the blood. Hurst 
(311) is the leading exponent of the streptococcus theory 
of the cause of the disease. Having first demonstrated that 
achlorhydria was as constant in “pure’’ cases of subacute 
combined degeneration of the cord as in pernicious ane- 
mia, he made cultures of the duodenal contents during 
life on 4 patients with the former and 7 with the latter 
form of the disease, and employed as controls 26 cases, 
either normal, or suffering from conditions without achlo- 
rhydria. Table 8 shows his results. 


TABLE 8 
Streptococcus longus in the duodenal contents, (Hurst) 


Number _S. longus 
of Cases present Percentage 


INO iin atl pees eas eee ce SE Ls 4 0 

Infective jautidice 2... 8 0 LES) 
Various medical cases ............---..- 14 3 

Pernicious) anemia 2008.02.40. 7 7 100.0 
sup Comb, Degen. Cord,, -.._..... 4 4 t ; 


No detailed description of the technique employed in 
this culture work has come to our notice, but accepting the 
results as stated to be bacteriologically beyond criticism, 
their interpretation is hazardous. Hurst concludes in part 
that the presence of Streptococcus longus in the duode- 
num is evidence of active infection of the intestine. This 
may be true but does not mean necessarily any tissue 
invasion. He leans rather to the view that this organism 
by decomposing unaltered protein gives rise to hemolytic 
and neurotoxic bodies which on absorption cause the dis- 
ease. To make such a hypothesis convincing the organism 
would need to be shown capable of forming such bodies, 
and these bodies would need to be capable of intestinal 
absorption. No records of this having been done appear. 
Experimentally the Streptococcus longus has not been 
shown capable, by tissue infection, of producing an 


74 PERNICIOUS ANEMIA 


anemia of the pernicious type. Hurst states, “In one of 
our patients an autogenous vaccine made from the S. 
longus isolated from the socket of an infected tooth gave 
rise to a temporary aggravation of the sensation of pins 
and needles in the hands and feet each time it was in- 
jected.’’ Cornell noted the same phenomenon when patients 
were injected with formalized or plain B. welchii toxin. 
Probably it is due to a non-specific protein reaction and 
of no great significance. Again, no serological reactions 
on pernicious anemia in connection with the streptococcus 
have been found, and anti-streptococcus serum exerts no 
beneficial effect on patients with the disease. This latter 
fact has been amply attested (55,632). 

Recently Moench, Kahn, and Torrey (448) found 
streptococci very numerous in the stools of thirty-three 
cases of pernicious anemia. The strains were of the nor- 
mal intestinal types, with no representatives of the hemo- 
lytic group being encountered. 

The B. coli theory. Adami (2) suggested in 1900 that 
in pernicious anemia “we deal with a subinfection by 
means of hemolytic intestinal bacteria of the colon 
group.” A similar supposition played a part in this auth- 
or’s explanation of hepatic cirrhosis. It means that these 
special strains of B. coli invade the intestinal wall, enter 
the portal blood, and then break down, somewhere in the 
body, liberating destructive endotoxins which are hemo- 
lytic and neurotoxic. Such a hypothesis defends itself in 
so far as it at once circumvents the difficulties inherent in 
an intestinal intoxication theory. It is plausible in that it 
specifies an organism abundantly present in the lumen of 
the gut. Moench, Kahn, and Torrey (448) were struck 
by the uniformly high counts for B. coli in the stools of 
pernicious anemia patients, being much higher than for 
normal persons or people with other pathological condi- 
tions. Lowenberg (387) recently showed, in culturing the 
duodenal contents, that B. coli was present in eighty-five 


ETIOLOGY 75 


per cent of cases of the disease and in only thirty-five per 
cent of cases of uncomplicated achlorhydria, whereas not 
nearly as great a discrepancy occurred between the two 
same groups with regard to the finding of enterococci 
(ninety per cent and seventy-five per cent respectively). 
Routine cultures of pernicious anemia organs at autopsy 
frequently show B. coli in the spleen and bone marrow. 
Percy (495), in cultures of organs made at laparotomy 
on spleens, gall bladders, and appendices of nine cases of 
pernicious anemia, found Streptococcus hemolyticus in 
seven cases, B. coli in five, Strept. viridans in four, and 
Stapholococcus albus in one. Experimentally Nyfeldt 
(476) by injecting rabbits intravenously with either the 
whole autolyzates or extracts of autolyzates of various 
intestinal bacteria, particularly B. coli, was able to pro- 
duce a blood picture and histological lesions resembling 
pernicious anemia in seven out of sixteen, while the other 
nine developed a simple anemia. 


OTHER DATA CONCERNING INFECTIONS 
Sellards finds frequently in spleens removed at oper- 
ation in pernicious anemia an anerobic bacillus resembling 
in all details that isolated by Plotz in typhus fever, but 
not bearing, in his opinion, any etiological relationship to 
the disease. 

Macora (392) has reported the finding of B. typhosus 
at autopsy in the spleen and bone marrow. Stanzani 
(588) has noted anemia of “pernicious type” at the 
height of typhoid fever. MacLean made a careful blood 
examination on twelve cases of typhoid fever in the 
Montreal epidemic, 1927, but was unable to make any 
similar observation, any anemia present being of a simple 
nature. Kline (343) has reported the finding of B. proteus 
in the bone marrow. Ecker and Brittingham (160) report 
the production of a hemolytic exotoxin from this 
organism. 


76 PERNICIOUS ANEMIA 


Wood (661) has found the monilia psilosis in the feces 
of fifteen cases of pernicious anemia, while from forty 
cases which were neither pernicious or sprue this yeast 
was not recovered. Experimentally by feeding this monilia 
to guinea pigs on normal diet, he produced a macrocytic 
anemia with hepatic siderosis and extension of the red 
bone-marrow with normoblast increase. Wood has been 
impressed, as has Elders (169), by the striking relation- 
ship between sprue and pernicious anemia. Musser (465) 
has emphasized the common finding of free HC1 in sprue. 
Fontaine (207), in discussing Wood’s paper, stressed the 
common finding of a simple anemia in sprue, the different 
type and greater incidence of diarrhoea in sprue, and his 
own inability to find the monilia in cases of pernicious 
anemia. The work of Wood is of great importance since 
he has demonstrated that, at least in the neighborhood of 
his clinic in North Carolina, many cases are seen in which 
either the diagnosis of pernicious anemia or sprue is 
equally justifiable, even when glossitis, achlorhydria, and 
cord lesions are adopted as diagnostic points. The writer 
feels that two factors are to be taken into consideration 
in this connection: (1) The blood picture of sprue itself, 
especially in the presence of severe anemia, bears a strik- 
ing resemblance to that of pernicious anemia. (2) Sprue 
is, in some unknown manner, capable at times of setting 
in motion the fundamental bodily process which is oper- 
ative in idiopathic pernicious anemia, and bears to the 
Addisonian complex the same provocative relationship as 
is possessed by the fish-tapeworm infection. In a country 
where sprue is common, it may constitute the “releasing” 
factor in pernicious anemia. 

Broun et al. (74) in experimental work with the M. 
psilosis could not produce a blood picture approximating 
pernicious anemia. By the use of an antigen prepared 
from the monilia some cases of pernicious anemia show- 
ing monilia in the feces gave positive complement fixation 


ETIOLOGY 77 


reactions, but so also did the sera of cases, other than 
pernicious anemia, who harbored the monilia. 

Logan (385) as well as Jennings (323) found Balan- 
tidium coli in the feces of a number of cases of pernicious 
anemia. Logan does not feel either that all cases of balan- 
tidium infection have pernicious anemia or that all cases 
of pernicious anemia have the balantidium. He (386) 
suggests the importance of a study of toxin production 
of humanized strains. 

Meessen (428) believed that he had demonstrated spi- 
rochetes in the blood of pernicious anemia, but Determann 
(146) later showed that what Meessen had considered 
motile spirillae were actually hemokones or “blood dust.” 

No evidence of a filterable virus has been reported. 


MISCELLANEOUS THEORIES 


The following hypotheses have never proved convinc- 
ing—Sahli’s (545) iron theory, Allport’s (10) “San- 
guinin” theory, and many theories specifying individual 
substances such as blood phenols (37). 


THE VALIDITY OF EXPERIMENTAL BLOOD PICTURES 

A large number and variety of agents can produce on 
parenteral injection blood pictures of macrocytic character 
bearing more or less resemblance to that of pernicious 
anemia—ricin, saponin, acetanilid, pyrodin, potassium 
chlorate, pyrogallic acid, glycerine, nitro-benzol, trinitro- 
toluol, toluodiamin, B. welchii toxin, oleic acid, and vari- 
ous tissue extracts. Some of these may cause a marrow 
reaction of megaloblastic type. This heterogeneous col- 
lection of agencies makes it clear that a macrocytic smear 
picture is not at all a specific phenomenon. Probably none 
of these pictures show the finer, and obviously necessary, 
features of that of pernicious anemia. Exposures over 
long periods to radium and X-rays give a similar though 
aplastic picture. It is unlikely that any proposed agent will 


78 PERNICIOUS ANEMIA 


receive serious consideration as the etiological agent 
unless it can produce, in addition to anemia, combined 
degeneration, glossitis, and achlorhydria. Moreover, if 
such an agent could fulfill these requirements it would 
not be absolutely certain that it was identical with a toxin 
presumed operative in the disease pernicious anemia, nor, 
indeed, would it render a toxin theory imperative. 


CONCLUSION 


Pernicious anemia appears to be a superstructure of 
blood-system and nervous-system changes superimposed 
upon an unknown but characteristically fluctuant foun- 
dation. Of this foundation we know nothing, but conceive 
of achlorhydria as its almost constant and only obvious 
expression. It is not impossible that several different 
factors may bring the unknown fluctuant process into 
operation. This process may depend upon idiosyncratic 
characters of the patient. The wide-spread tissue involve- 
ment found and the peculiar mass of biochemical changes 
suggest that this fundamental process is a disturbance 
of metabolism. 


CHAPTER IV 
GENERAL SYMPTOMATOLOGY 


While the digestive, blood, and nervous systems pro- 
duce the chief and specific symptoms, every system except 
the articular is appreciably involved. Physiologically every 
tissue of the body must suffer from the disturbed metab- 
olism known to exist. Any conception of the disease is 
inadequate which neglects its wide-spread bodily conse- 
quences. The clinical manifestations, while expressive of 
this extensive involvement, are nevertheless in general 
painless, mild, and surreptitious in proportion to the debil- 
ity produced and to the culmination which, until the pres- 
ent at least, has been almost invariably fatal. No disease 
shows, of necessity, all its symptom possibilities in any one 
case, nor does it marshal its symptoms necessarily in any 
given order of appearance. With this concession one must 
admit that pernicious anemia is a clinical entity. Vari- 
ations are those of time and degree, but not of kind. Blood 
abnormality, nerve tissue degeneration and digestive tract 
disorder constitute the entity, and no known disease pre- 
sents a more constant quantum than this triad of symptom 
groups. Most arguments to the contrary arise from a 
resemblance of one of these elements (blood abnor- 
mality) to that found in a few other conditions. The 
specificity is constituted by the quality but especially by 
the association of these three system processes. The blood 
abnormality, in its strict identity, is but seldom success- 
fully mimicked by other diseases. The type of nerve-tissue 
degeneration, while sporadically occurring in several 
other conditions, occurs most frequently by far in associ- 
ation with pernicious anemia. The digestive tract phenom- 
ena, though not understood, are constant and, when 
glossitis occurs, specific. The gathering together of these 
three great system processes forms a strange disease, re- 


[79] 


80 PERNICIOUS ANEMIA 


sembled by nothing else in animal pathology and deserv- 
ing to stand, for the present if not the future, as a definite 
entity. So slight are the deviations from the fixed type, 
and so constant are the total reported manifestations over 
a period of a century, that any attempt to subdivide the 
idiopathic disease into separate entities, on a clinical or 
pathological basis, would appear unwarranted. 


THE HISTORY OF THE PATIENTS 


One must subscribe, in part at least, to the thesis that a 
particular type of individual is the most prone to acquire 
the disease. They are usually large framed persons with 
considerable subcutaneous fat, fine grey hair, carious 
teeth, and blue irides. Usually they possess a sensitive 
mentality. Exceptions occur frequently enough, but the 
rule stands. No group of patients could have pleased more 
the fancy of the staunch clinicians of the past century, 
who laid so much store by diathesis. Translating this 
word into the more modern expressions, type and consti- 
tutionality, our century is delving into this difficult phase 
of the study of disease with calipers and the entire arma- 
mentarium of modern medicine to determine by actual 
measurements if definite types and constitutions really 
do tend to develop certain diseases more regularly than 
others. Draper found certain acromegalic characteristics 
in the “pernicious anemia people” and this, coupled with 
the phenomenon of familial occurrence suggests that, in 
many instances, our cases develop in individuals of a 
peculiar constitutionality. The occurrence of achlorhydria 
prior to the onset of pernicious anemia has been so fre- 
quently reported that it is now considered probable that 
most cases have previously been achlorhydric, either from 
birth, or at least for many years. This may or may not 
bear some relation to the dyspepsia or diarrhoea volun- 
teered by some cases as a symptom of long duration 
antedating their illness. 


GENERAL SYMPTOMATOLOGY 81 


A hemorrhagic tendency is sometimes noted in the past 
history, such as bleeding hemorrhoids or uterine oozing, 
perhaps without demonstrable uterine lesion. This may 
be due to impaired coagulation of the blood or changes in 
the walls of the blood vessels. While the continuous loss 
of blood over long periods may appear to be an etiological 
factor in pernicious anemia later developing, such a fac- 
tor is sufficiently unusual to be credited with little more 
than exerting a functional strain, slight or severe as the 
case may be, upon the hemopoietic tissues, and of assum- 
ing, therefore, but a secondary contributory role, com- 
parable to that of sepsis, in the production of the specific 
anemia. 

Occasionally the operation of gastrectomy has pre- 
ceded the onset of pernicious anemia, in which case the 
obvious inference is made that by artificially instituting 
an achlorhydria one has placed the patient in a parallel 
position with other victims whose achlorhydria was the 
result of constitutional or physiological causes. As Piney 
(499) has pointed out, however, this surgical operation 
is usually performed for new growth, and in every case 
subsequently developing alleged pernicious anemia, metas- 
tases to the bone marrow must be considered. 

Chronic alcoholism may be prominent in the history, in 
which case it may have operated, as Hurst (307) sug- 
gests, by establishing an achlorhydria. 

By no means infrequently, a history of some abdominal 
disorder presents itself. This includes chronic stenosis of 
the digestive tube at various levels—the so-called “stric- 
ture anemia.” The writer saw a case of Hanna’s in which 
the disease followed oesophageal stricture from drinking 
carbolic acid. Tumors of the stomach and colon are also 
noted. In all such cases it is questionable how much influ- 
ence these lesions play in the etiology. 

It is the general experiance of clinicians that the great 
majority of patients, prior to the disease, have enjoyed 


82 PERNICIOUS ANEMIA 


fairly good health and that the onset, however judged, 
was more or less sudden. Until the inception of their ill- 
ness they may be regarded as cases of uncomplicated 
achlorhydria. More careful inquiry may in many instances 
elicit the fact that some particular feature of the disease 
was actually present for months before the patient began 
to be conscious of anything wrong. This applies particu- 
larly to the sore tongue. The neurological manifestations, 
especially numbness and parasthesiae, quite often appear 
first and may remain uncomplicated by blood abnormality — 
for months. 

But the glossitis and numbness are really part and 
parcel of the established disease and, in patients present- 
ing either of these features independently, the additional 
discovery of achlorhydria should make the diagnosis pos- 
sible even before any anemia exists. 

In the majority of cases, weakness is the initial com- 
plaint and depends on the initial manifestation, viz., 
anemia. . 

In a fraction to be estimated at twenty to thirty per 
cent of the total, the patients confess that they have not 
been really well for months or even years beforehand, 
although none of the recognisable features of the estab- 
lished disease have been present. This prodromal debility 
may have consisted of an apprehensive neurosis border- 
ing on a psychosis. The writer recalls a patient who, for 
one year previous to developing pernicious anemia, drove 
his wife nearly to distraction by his introspective mood, 
his lack of business stability, and his never-ending quest 
of medical help from every doctor suggested to him. He 
had achlorhydria, pyorrhoea of a moderate degree, and a 
mild simple anemia due possibly to oral sepsis. Another 
patient, a married woman of forty, spent all her spare 
money on specialists although the reports on the heart, 
lungs, and nervous system all came back significantly 
negative. She was determined that something dreadful 


GENERAL SYMPTOMATOLOGY 83 


was in store for her and the ultimate diagnosis of perni- 
cious anemia acted almost as a relief to her state of appre- 
hension. A third patient, though apparently a healthy man 
of forty-two, spent most of his time in bed or in his bed 
room for one year previous to the diagnosis, being quite 
disarmed to meet the world by his private conceptions of 
his own condition. 

But where the patient, prior to the disease, has been 
definitely under par, there have usually been present very 
definite symptoms referable to the digestive tract, par- 
ticularly an intractable diarrhoea, to which further refer- 
ence will be made. 


THE ONSET OF THE DISEASE 


The disease may declare itself gradually, revealing par- 
tial glimpses of its whole self over some months, so that 
the diagnosis may dawn on the physician as the true ex- 
planation of a tedious association with a vague condition. 

Again, it may begin suddenly in a seemingly healthy 
person with a moderate rise in temperature (101°) and be 
regarded as influenza until the pallor of the pigment- 
stained sclerotics suggests an examination of the blood. 

A high seasonal incidence during the summer months, 
July to September, has been observed by Hunter (301) 
and by Bartlett (29). Schauman and Saltzman suggest 
that the confining winter, with lessened sunshine, limited 
exercise, and comparative absence of green vegetables and 
fruit are sufficient to precipitate a potential breakdown. 
Spring pneumonia, tonsilitis, and neurasthenia are famil- 
iar to every practitioner. 

Unfortunately patients are seldom seen by physicians 
at the time of the onset of the anemia. It is to be under- 
stood that whereas the onset of the disease is usually a 
gradual process, there must be a time, in every case, where 
the blood count and the hemoglobin percentage actually 
begin to decline. Since weakness is the commonest symp- 


84 PERNICIOUS ANEMIA 


tom which takes patients to doctors, and since weakness 
is due largely to anemia, the patients are usually quite 
anemic when first seen, with depressed numerical counts 
and with smear pictures characteristic of the disease. 


THE COMPLAINT OF THE PATIENT 


The great majority first consult the physician for 
weakness alone, although weakness is nearly always pres- 
ent to some extent even if the complaint is different. The 
next largest group consist of those who complain either 
of numbness or tingling in the extremities, of glossodynia 
or of dyspnoea. A smaller group still come on account of 
dyspeptic symptoms (belching, heaviness, vomiting, nau- 
sea, diarrhoea) and are occasionally diagnosed as cases 
of cholecystitis, a condition which is sometimes present, 
while many have been explored abdominally for appendi- 
citis or gastric ulcer. Other more unusual complaints have 
been noted, such as girdle pains, arthralgia, failing vision, 
dizziness, lack of mental concentration, hematemesis, 
hemorrhage from the bowel, and, strange as it may seem, 
retention of urine from advanced cord change. 


OUTLINE OF THE SYMPTOMS AND SIGNS 


Among the general symptoms, not particularly refer- 
able to any one system are fever and loss of weight. 

Fever, except in hospital patients, may not be much 
noted. Temperature charts of patients during severe 
phases usually show an elevation of some type. It may be 
irregular and seldom rise above 99.5° F, suggesting a low 
grade septic condition. It may show daily swings from 
97° to 101° and remain thus for days hand-running. 
Again, it may be sustained around 99.5° to 101°. The 
presence of such fever has sometimes suggested typhoid 
or secondary syphilis. Some cases may begin with a fever 
as high as 101 F. Higher temperatures may occasionally 
be noted, especially in the chronic hemolytic anemia of 


GENERAL SYMPTOMATOLOGY 85 


pregnancy, which may reach an elevation at times of 
106° F. The cause of fever in pernicious fever is unex- 
plained. During remissions the temperature is either 
normal or subnormal. A transfusion of blood does away 
with any fever that may be present. 

The weight does not, as a rule, suffer as much decrease 
as would naturally be expected. The panniculus adiposus 
remains well preserved, giving the patient the well nour- 
ished appearance which, since the time of Addison, has 
remained one of the diagnostic features. It is a fallacious 
guide, however, since, as pointed out by Cabot (91) and 
by Bloomfield (50), some loss of weight occurs in forty 
per cent of cases. Minot (440) has noted that weight is 
not infrequently lost during relapses and regained again 
during remissions, and cites the instance of a man weigh- 
ing one hundred and eighty pounds who had twelve rather 
rapid relapses and remissions. In the first five relapses he 
lost between thirty-five and fifty pounds and returned to 
one hundred and eighty pounds with each remission. 
While at abdominal operations a substantial layer of 
bright yellow fat is usually seen in the abdominal wall, 
there is little doubt that some of the weight of these pati- 
ents is due to abnormal amounts of fluid in the tissues. 
In cases characterized by dehydrating diarrhoea, marked 
loss of weight occurs, but is quickly regained when the 
diarrhoea ceases. 

“The anemia itself sufficiently accounts for dyspnoea, 
palpitation, muscular weakness, mental irritability, dizzi- 
ness, and syncope. 

Glossitis, pyorrhoea, stomatitis, achlorhydria, anorexia, 
nausea, vomiting, and diarrhoea are referable to the 
digestive tract and will be discussed thereunder. 

The blood data, including features connected with the 
blood condition, such as weakness, the color of the patient, 
the enlargement of the spleen and liver, and the problem 


86 PERNICIOUS ANEMIA 


of the pigment metabolism will be dealt with in the chap- 
ter on the blood system. 

Numbness, parasthesiae, spastic gait, paresis, ataxia, 
girdle pains, abdominal crises, and psychoses are refer- 
able to the nervous system and will receive attention in 
chapter VIII, while the changes found in the cardio-vas- 
cular, respiratory, and genito-urinary organs will be con- 
sidered in a separate chapter. 


DIFFERENT CLINICAL TYPES OF THE DISEASE 


The differences, sometimes clearly marked, to be seen 
in a clinical study of a group of cases, usually depend 
upon the fact that sometimes one system, sometimes 
another, presents the first symptoms, or presents some 
unusually striking symptom. Martin (404) presents three 
cases in one ward, the first showing sore tongue for 
eighteen months before anemia began, the second case 
starting with a virtual transverse myelitis and simple 
anemia, the third showing a rapid and grave hemolytic 
anemia with such marked muscular atrophy as seen in 
chronic poliomyelitis. Martin’s fourth case presented the 
blood picture of pernicious anemia and a foul mouth, but 
no other signs of the disease, and became normal after 
the removal of apical tooth infection. It is suggested that 
such cases as this last ought to be regarded as severe 
septic anemia and not diagnosed as pernicious anemia on 
the blood condition alone. Stern (593) presents four 
cases, in the first of which the drainage of an infected 
gall-bladder caused improvement a case of infection with 
dibothrio cephalus latus, a case with the nervous symp- 
toms preceding, and, last, a case of syphilis which was 
seen not to be pernicious anemia at autopsy. Unquestion- 
ably these are clinical varieties of severe anemia, but not 
all of pernicious anemia, a term used in a restricted sense 
to indicate a cryptogenic entity. 


GENERAL SYMPTOMATOLOGY 87 


Whereas many of the so-called clinical types recorded 
are not instances of true pernicious anemia, and therefore 
the division into clinical types becomes less interesting, 
Archibald (13) as well as Minot and Lee (446) have 
suggested the only fundamental division of the disease 
into types. This division is based upon the balance main- 
tained between blood destruction and blood regeneration 
and is equivalent to a division on the basis of the course 
of the disease. This will be presently considered in the 
chapter on the blood system. 


CHAPTER -V 
THE DIGESTIVE SYSTEM 


Previous to 1890, special descriptions of the digestive 
system had been made in only nineteen cases, and by 
fourteen different observers, one of whom, Hale White 
(249), was responsible for six of the cases. Hunter alone 
by 1903 had made careful observations on twenty-five 
cases with histological examination of the digestive 
organs on seven, and by 1909 he had increased the series 
by fifty. Now that digestive signs and symptoms are 
regarded as inseparable from the disease, the paucity of 
the early observations seems surprising. Obtrusive as 
these manifestations sometimes appear, they are at other 
times very subordinate. The attitude of the early students 
is therefore not difficult to understand. If digestive symp- 
toms were mild they were regarded as secondary to the 
anemia ; if severe, they were considered as causative. This 
alternating viewpoint may be traced through most of the 
early articles. Anatomically, the intrinsic difficulties have 
caused a half century of indecisive descriptions, but more 
recently our position has become somewhat more stabi- 
lized. Physiologically, the observations on achlorhydria, 
begun in 1886, have been amply increased, and now con- 
stitute the most solid ground in the entire subject. 

In Combe’s (128) case the gastro-intestinal symptoms 
were very marked. Addison (5) noted the anorexia. In 
one of his cases in 1857, healed ulcers were found in the 
colon and rectum. Barclay (22) in 1851 reported a case 
with diarrhoea and sore mouth. Biermer (60) in 1871 
noted follicular ulcers of the colon. From then until 1900 
the chief observers were Fenwick (199), Flint (205), 
Ponfick (502), Schauman (553), Burger (83), Miiller 
(459), Quincke (510), Ejichhorst (165), Nothnagel, 


[ 88] 


Tae DIGESTIVE SYSTEM 89 


Bramwell (63), Nolen (474), Laache (351), Pye-Smith 
(507), Henry and Osler (265), Cahn and von Mehring 
(94), Lewy (371), Kinnicutt (377), Rosenheim (536), 
Hunter (292), Ewald (259), Hale White (249), Mader 
(393), Mott (456), Halt, Eisenlohr (167), Nonne 
(472), Hayem (259), Pepper and Stengel (494), Mar- 
tius (406), Grawitz (220), Koch, Fletcher (204), Faber 
and Bloch (185). 

The chief point of contention has been the question of 
gastric and intestinal atrophy. Glossitis has been assigned 
a definite place in the symptomatology. Achlorhydria has 
been recognized as almost a sine qua non in the diagnosis. 
This, in very brief outline, covers the trend of events in 
the investigation of this particular system. 


SYMPTOMS AND SIGNS ARISING FROM THE 
DIGESTIVE TRACT 


At least eighty per cent of patients have symptoms 
referable to this system. Practically all patients have 
achlorhydria. The statement is therefore justified that the 
digestive system always presents some abnormality. 

French (211), inan analysis of sixty-eight consecutive 
cases in Guy’s Hospital, found that 


45 had gastro-intestinal symptoms, 
20 had chronic or recurring diarrhoea, 
7 had gastro-intestinal symptoms dating back five years or 
more before the onset of the anemia. 


Thus,— 


Case 5, aged 57, had abdominal pain and diarrhoea since age of 13, 
Case 7, aged 44, had abdominal pain and diarrhoea since age of 19, 
Case 8, aged 51, had abdominal pain and diarrhoea since age of 25, 
Case 11, aged 56, had diarrhoea with bloody stools for five years 
previously, 

Case 17, aged 50, had diarrhoea for seven years previously, 

Case 36, aged 32, had diarrhoea for seven years previously, 

Case 38, “Bowels loose ever since he could remember.” 


90 PERNICIOUS ANEMIA 


An analysis by Panton et al. (482) of one hundred and 
seventeen cases showed a distribution of digestive symp- 
toms as follows: 

Vomiting in 51, 

Diarrhoea in 30, 

Anorexia in 26, 

Epigastric pain in 24, 

Painful tongue in 8, 
Pyorrhoea in 47 out of 93, 
Carious teeth in 10 out of 93, 
Achylia in 33 out of 35, 
Hematemesis in 3, copious in 1. 


They state that in certain of their cases diarrhoea formed 
the prelude to the train of symptoms. 

The question of the relative frequency of digestive 
signs and symptoms to those of other systems, may be 
settled by the fact that achlorhydria is practically always 
present, whereas signs or symptoms of nervous involve- 
ment occur in eighty-four or eighty-five per cent of cases, 
and blood abnormality may be absent in ten per cent with- 
out preventing the diagnosis. Neglecting achlorhydria 
for the moment, even the other signs and symptoms are 
equally frequent with those of nervous involvement and 
almost as frequent as blood changes. But including 
achlorhydria, which is justifiable, the conclusion is quickly 
reached that gastro-intestinal changes are the most con- 
stant, and indeed the earliest, in the disease. Their virtual 
constancy in the face of possible absence of nervous or 
blood changes is the best argument for the popular gas- 
tro-intestinal conception of the etiology, and sufficient 
justification for those to whom the problem of nutrition 
assumes causal proportions. 

The symptoms, glossitis, pyorrhoea, stomatitis, anor- 
exia, nausea, vomiting, and diarrhoea will be considered 
in some detail, and in connection with the causative or the 
physical basis, if any, upon which each appears to rest. 


THE DIGESTIVE SYSTEM 91 


THE MOUTH, ITS CONTENTS, AND THE OESOPHAGUS 


The symptoms arising from these organs are glosso- 
dynia, sore mouth and painful deglutition. The signs are 
glossitis, atrophy of the tongue, small ulcers and hyper- 
emia of the buccal mucosa, pyorrhoea alveolaris, dental 
caries, root abscess, and, presumably, oesophagitis. 

The first mention of the mouth condition is contained 
in a case-report by Barclay (22) in 1851. “Soon after 
her confinement she had sore mouth for which she applied 
for advice, and was ordered to leave off beer and meat, 
and confine herself to slops. To this she attributed her 
debility, as she had continued to suckle her child and had 
never been able to get up her strength properly.” 

Miller (459) mentioned five cases out of his series of 
sixty-two in which “there was a peculiar stomatitis. 
Small whitish ulcers, the size of a split pea, formed in 
the mouth, especially on and under the tongue. These 
were very resistant to local treatment, disappearing 
spontaneously or with remissions, but recurred without 
special reason, to the great discomfort of the patient, 
since they were decidedly painful and made mastication 
difficult or impossible.” Miiller connected these lesions 
with the blood state, assuming that some chemical sub- 
stance was secreted into the mouth, which by admixture 
with the saliva produced an irritating fluid. 

Quincke (510) noted redness and soreness of the 
tongue in some of his cases. Eichhorst (165) in one of 
his own seven cases found painful fissures on the dorsum 
of the tongue. Laache describes graphically some vari- 
ations of the stomatitis in three of his eleven cases. In 
one, the tongue had lost its papillae and, though smooth 
and clean, was hacked and painful at the borders. Both 
angles of the mouth were excoriated. Some of the teeth 
had fallen out and the rest were carious. This patient 
complained not so much of weakness as of sore mouth, 


92 PERNICIOUS ANEMIA 


of loss of taste and the sense of smell. Another patient 
complained that not only was his mouth sore, but the 
soreness extended down the throat and prevented him 
from taking hot or hard food. Ewald (179) hesitated 
with regard to naming this condition. He considered the 
terms erythema bullosum, chronic neurotic stomatitis, 
pemphigus, herpes, and finally decided that follicular 
stomatitis was most appropriate. 

Hunter (292), beginning as early as 1889, has written 
extensively on the mouth condition, and has done more 
than all others combined to familiarize the profession 
with the occurrence of oral sepsis and to delineate the 
features of the glossitis. Perhaps no one has actually con- 
firmed Hunter’s statement that glossitis occurs in every 
case. Again, his deduction that the glossitis is due to the 
activity of a specific micro-organism responsible for the 
disease, cannot be accepted except as an obvious hypothe- 
sis. He believes that the glossitis is an emblem of the 
gastritis and enteritis (?) of the disease, all being caused 
by an unknown organism, whose chief characteristics are 
its ability to produce a periodic local reaction with com- 
paratively little permanent scarring, and to shift its 
activities downward so as to affect various regions of the 
digestive tube successively. He believes, moreover, that 
septic infection, particularly by a long streptococcus, is 
the antecedent event which prepares the tongue, the stom- 
ach, and perhaps the intestine for the reception of the 
hypothetical organism. He is persuaded, as everyone 
must be, that septic infection can, and usually does, occur 
in the mouth without the peculiar glossitis so common in 
this disease. 

During the past twenty-five years, the glossitis has 
been sufficiently observed and confirmed by others to 
merit its position as one of the specific features of the 
disease. Such confirmation comes from French (211), 
Christian (111), Houston, Willson (658), Hurst (307), 


THE DIGESTIVE SYSTEM 93 


Symmer (605), Elders (169), Evans (177), Panton et 
al. (482), and others. Minot (440) would estimate its 
occurrence at forty-five per cent or slightly higher. Will- 
son and Evans (657) found it in only twenty-one per 
cent of the Johns Hopkins Hospital series. Osler (477) 
admitted he had not seen it at all commonly. Panton et al 
(482) found a painful tongue in eight out of thirty-four 
patients questioned; it was the first symptom in three of 
these; and they claim to have seen the typical glossitis 
in one case other than pernicious anemia. Some clinicians 
have noted a similar tongue condition in cases of arterio- 
sclerosis. 

The tongue in pernicious anemia is invariably smooth, 
clean, and moist. Evans (177) remarks: “A coated 
tongue and a diagnosis of pernicious anemia is a combi- 
nation to excite suspicion.” Coated tongues, even heavily 
furred ones, are common in certain hemolytic anemias, 
especially when the patient is very ill; but, as Evans also 
remarks, cases of pernicious anemia come to the autopsy 
table with tongues devoid of coating. The other features 
of the tongue depend upon the stage of the disease at 
which they are seen. In the most active stage of the glos- 
sitis, which may occur before any anemia is present, or 
during a first attack or a remission, the organ, on pro- 
trusion, appears fiery, deep red, sometimes of a crimson 
or carmine hue, and justifies the common description of 
“beef-steak” tongue. At this stage it may be painfully 
fissured in an irregular manner near the tip or along the 
median line. The whole organ may appear edematous with 
indentations along its border from pressure of the teeth. 
It is moist and glistening and may or may not be com- 
plained of. When it is lifted, the veins on the inferior sur- 
face are frequently engorged and varicose. Vesicles filled 
with serum may occur near the tip on either surface. At 
times when the blood is impoverished and all the mucosae 
are pale, the tongue presents a definite pallor, except along 


94 PERNICIOUS ANEMIA 


the edges where a mottled reddish appearance is found. 
Often, at such times, on the dorsum, are areas roughly 
five millimeters in diameter, quite pink or reddish from 
local congestion. Simple ulcers with straight or shelving 
edges, three millimeters in diameter, or slightly larger, 
and with seropurulent bases, may occur on the tongue 
borders, on the buccal surfaces of the cheeks, or in the 
anterior walls of the vestibulum oris, reminding one of 
so-called cankers constitutionally occurring at times in 
healthy individuals. Finally there is the small-appearing, 
ironed-out, atrophic tongue with papillae dwarfed or 
absent, occurring well on in the disease, subject even still 
to periodic attacks of soreness and marginal redness, but 
quiescent,—a permanent hall-mark of the disease, and of 
equal clinical significance to the permanent macrocytosis 
sometimes persisting in patients with remissions of 
twenty years’ duration. 

Newham, Morris, and Manson-Bahr (471) emphasize 
as the really specific features of the glossitis the follow- 
ing points: general destruction of papillae, raw dorsal 
surface, general glossy appearance, and fissuring at the 
periphery of the organ. 

The description by the patients of their sensations vary 
from a mere confession of sore tongue to comparisons 
of many kinds. “Tongue raw and tender, looking like a 
piece of raw liver—causing great pain’ (Hunter). “As 
if rubbed with sandpaper.” “As if I had burnt it with hot 
tea.” “Feels raw, as if it had been cut.” Eating frequently 
becomes difficult, the tongue being especially sensitive to 
acid foods, sometimes to all foods. It is noteworthy that 
mouth washes, painting with argyrol, or other forms of 
local treatment are usually not helpful. 

The symptom is quite variable in its time of onset, and 
always marked by an irregular periodicity during its 
course. On the whole it is most troublesome and severe 
in the early stages of the disease, and much less so, or 


THE DIGESTIVE SYSTEM 95 


absent, in the later stages. It may remain sore for 2 or 3 
weeks at a time, then be comfortable for a month. Again, 
it may remain sore more or less continuously for months 
at a time, being worse on certain days than others. Hunter 
found the sore tongue more troublesome during remis- 
sions than relapses. Certainly it is often far from com- 
fortable during periods of remission and may, at such 
times, be volunteered as the only complaint. A clergyman 
in whom the symptom proved unusually annoying, habi- 
tually purged himself to gain temporary relief. 

As is well recognized, and as pointed out by Riesman 
(523), Schafer (549), and Strieck (603), glossitis may 
be the initial manifestation of the disease and exist for 
at least several months without other definite signs. Ries- 
man (523) has spoken of it as an inaugural symptom and 
records three such cases. The first was that of a woman 
of 54, complaining of a biting, stinging sore tongue. The 
normal coating had disappeared, leaving it raw and ten- 
der. The burning sensation spread to the inner surface of 
the cheeks and lips. As time went on, the tongue was 
chiefly affected and became streaked with red lines. She 
said it felt “as if it had been scraped and had no top.” 
Food tasted queer, and the character of the food made 
little difference. The tongue was carmine colored and 
tender to the touch. A small ulcer appeared on the left 
buccal cheek surface. The teeth were in moderately good 
condition. The blood counts were normal although some 
anisocytosis was present. Riesman prophesied she would 
develop pernicious anemia and the patient obliged him by 
later dying of it. 

He reports a second case of a woman with well-cared- 
for teeth who complained of a sore tongue, though it was 
never coated or ulcerated, for 3 years before the symp- 
toms of pernicious anemia began with weakness, at which 
time the tongue ceased to trouble her, but looked pale, 
small, atrophic, smooth, without coating, and showed en- 
tire disappearance of the papillae. 


96 PERNICIOUS ANEMIA 


In a third case, diagnosed at first examination as per- 
nicious anemia, the patient confessed that for two years 
previously she had had a severe pain in the tongue and 
it had felt as if ulcerated, being worse in summer but not 
troublesome at the time of the examination. 

Riesman justly regards idiopathic glossitis as a fre- 
quent inaugural sign of pernicious anemia. Since this 
feature has been more carefully looked for, most city 
hospitals have one or more instances of patients seeking 
relief at the out-patient department for glossitis, and 
finally being located, after a number of months, in the 
wards with a diagnosis of pernicious anemia. 

The writer was told by a patient that six months before 
the first diagnosis, he had decided one evening to stop 
smoking, since although he had been trying new brands 
of cigars for two weeks previous to this on account of a 
sore tongue, the cigar he tried to smoke this particular 
evening hurt his tongue so severely that all pleasure was 
taken away from the habit. 

A married woman of 34, a patient of the writer’s, not 
seen for four months, at which time her only complaint 
was nervousness, stopped her car beside him on the street 
one day and asked if he could “do anything for a sore 
tongue.”’ He inquired if she had any other complaints. 
Pointing to her right foot she said: “It’s becoming so 
numb I can scarcely work the brake.” That afternoon her 
blood was examined. The hemoglobin was 60 per cent 
of normal, the red blood count was 5,000,000 per cubic 
millimeter, but the smear picture was perfectly character- 
istic of pernicious anemia. The patient said not only her 
tongue but her throat had been sore for two months be- 
fore this examination, but that the numbness in the foot 
had been noticed for only two weeks. A male cousin of 
this lady, himself suffering from pernicious anemia, had 
a sore tongue for three months before consulting a phy- 
sician for weakness. A man, 64 years old, president of an 


THE, DIGESTIVE SYSTEM 97 


industrial company, continued to attend executive meet- 
ings for three months when his tongue was so sore that 
he could scarcely talk, although during this period fre- 
quent examinations showed absolutely no abnormality of 
the blood. Finally his hands and feet became numb and 
the blood condition heralded itself with marked anisocy- 
tosis. 

While glossitis may be the inaugural symptom and ap- 
pear for months previous to the recognizable disease, 
there are many cases who never recall having experienced 
the symptom at any time, although even in these cases 
examination may show the uncoated, smooth, atrophic 
organ. Occasionally one sees normal appearing organs 
with which only imagination could detect any fault. 

While the cause of this glossitis is obscure, its local ap- 
pearance,—hyperemia, vesiculation, mucosal and muscu- 
lar atrophy,—suggests a local infection. Microscopically 
even in tongues little complained of, there are found, post 
mortem, areas of marked mucosal atrophy with subjacent 
chronic inflammation. At certain points the mucosa has 
entirely disappeared. In mild cases the muscle remains 
normal. In severe cases, extreme muscular atrophy has oc- 
curred, the fibres being replaced with fatty connective 
tissue. Hunter from the interior of such tongues obtained 
pure cultures of a virulent, long streptococcus, and con- 
sidered this organism to be responsible for at least part 
of the glossal manifestations. 

The periodicity of the symptom suggests that if an or- 
ganism is responsible, it is a type of infection character- 
ized by a tendency to light up and subside, and to migrate 
from one portion of the digestive tract to another. 

The other view of the pathology would regard any 
micro-organism found as a secondary invader, and the 
atrophy as either due to body-wide metabolic disturbance, 
or to a chronic toxemia by a hypothetical poison responsi- 
ble at once for all the digestive, nervous, and blood abnor- 
malities. 


98 PERNICIOUS ANEMIA 


Whatever may be the significance of the fact, the 
dental condition of patients with pernicious anemia is re- 
markably bad in most cases. It is the rare exception to 
encounter a case whose teeth do not show evidence of 
pyorrhoea. Once again, the exception robs the rule of any 
imperative significance, for pernicious anemia may de- 
velop in persons whose teeth are clinically and roentgeno- 
graphically normal, although it seldom does so. 

A serious simple anemia may result from root abscess 
alone, and may be cured by removal of the focus. On the 
other hand, persons with extreme pyorrhoea and filthy 
mouths and apical abscesses may show neither anemia nor 
any symptoms of ill-health. The whole factor of sepsis is 
to be considered in pernicious anemia as a frequent, but 
not imperative, influence bearing on the disease. Cases 
of pernicious anemia with removable sepsis, respond, 
after its irradication, by being less ill, showing fewer 
gastric symptoms, living longer, and exhibiting a more 
purely “‘pernicious” type of anemia. 

Not only the tongue, but, as stated, the buccal mucosa 
may show the peculiar reaction of which glossitis is the 
type. Some cases suffer from a persistent sore throat, and 
examination may reveal so marked an injection of the 
faucial pillars, the uvula, and soft palate as to suggest “in- 
fluenzal sore-throat.”” Presumably a similar reaction oc- 
curs at times in the oesophagitis as evidenced by the burn- 
ing sensation on swallowing. The writer has now under 
his care two first cousins, both with red hair, both 35 
years of age, both acquiring pernicious anemia in the 
same year, though living 100 miles apart, and both suffer- 
ing conspicuously from glossitis, sore throat, burning on 
swallowing, and indigestion characteristic of gastritis, 
Both have achlorhydria and they are progressing at about 
the same rate. 

According to Schwenkenbecker (569) a type of dis- 
turbance similar to the glossitis may affect the nasal 
mucosa. 


THE DIGESTIVE) SYSTEM 99 


Anorexia, nausea, and vomiting might be rationally ex- 
plained in the adynamic stages of the disease by the gas- 
tric atony known to exist. But these dyspeptic symptoms 
may, and frequently do, appear early, sometimes even 
before any diagnosis is possible. When of marked inten- 
sity and accompanied by fever and sweating, they give 
the most impressive picture ever seen in pernicious ane- 
mia, of an acute intoxication. 

The anorexia is usually at first of the nature of a mild 
aversion to certain types of food. In a few cases persons 
have been seen to change in their tastes, so that whereas 
ordinarily they were heavy meat eaters, they now become 
attracted more to sweet articles. Some, from being nor- 
mal eaters, become what dietitians call “tea and toast’’ 
people. Others become whimsical and “picky”. While 
some declare a special repugnance to pork and fats, more’ 
seem to specialize on fats. In a few instances, the anorexia 
is a positive abhorrence of all food, and it is only by the 
greatest art and tact, that even small amounts of nourish- 
ment can be given them. Under such circumstances as 
these, when the disease is fully established, it is quite 
evident that undernourishment or unbalanced diets have 
every opportunity to play what rdle they may in the total 
etiology. 

The tastes of these patients, however, during health 
and before falling ill, judged by a detailed study of their 
pre-disease diets over a decade, do not appear to differ in 
any remarkable way from those of their associates. In a 
recent survey conducted by the writer, it was found that 
from an absolute standpoint they were low in total calor- 
ies, high in fat, and lacking in protective foodstuffs. But 
it is questionable how many persons’ diets, in any com- 
munity, could bear the scrutiny of an expert dietitian, and 
it is reasonably certain that the 26 patients whose diets 
were examined were not more remiss than other persons 
in their vicinity who remained in health. The problem of 


100 PERNICIOUS ANEMIA 


diet, as an etiological possibility cannot, however, be so 
easily dismissed. The aphorism “‘what is meat to one may 
be poison to another” may indeed find a potential appli- 
cation in pernicious anemia, where, owing to a peculiar 
constitutionality, expressed in the achlorhydria, the diges- 
tion of food may well prove to be of greater importance 
than the choice of menus. 

Nausea and vomiting are not really common. They 
occur most in the same cases that present diarrhoea. They 
have no essential connection with pernicious anemia, and, 
as Hunter (306) and Percy (495) have demonstrated, 
they depend in many cases upon disease of the teeth, gall- 
bladder, appendix, or benign conditions of the intestine, 
such as stenoses, and improve or disappear after the re- 
moval of the diseased tissues. It is permissible to regard 
them, in the majority of cases, as due to associated sepsis. 
They are probably not due to the achlorhydria, any more 
than the achlorhydria is due to the sepsis, for many vic- 
tims have had symptomless achlorhydria long before any 
evidence of sepsis or pernicious anemia appeared. 

Epigastric pain, fullness, and heaviness are not unusual 
symptoms. The pain, or burning sensation in the stomach 
often conforms to the type of symptoms noted in uncom- 
plicated cases of gastritis, presents no time relation to the 
taking of food, and may be entirely relieved by irradica- 
tion of foci of infection in the mouth or accessory air 
passages. Again, the gastric symptoms, the history and 
the anacidity, when the patient is observed prior to the 
onset of the anemia, may suggest cholecystitis, and opera- 
tion not only proves the diagnosis to be correct but rids 
the patient of symptoms. Some months later, all the mani- 
festations of pernicious anemia bring the patient back to 
the medical side of the hospital. Not only so, but even 
after the disease is plainly recognizable, cholecystitis, if 
it be kept in mind, may occasionally be detected, justifi- 
ably diagnosed, and the gall bladder removed with benefit 


THE DIGESTIVE SYSTEM 101 


to the patient. Jones and Joyce (327) have reported 
thirteen cases of pernicious anemia in which the clinical, 
surgical, and post mortem findings established the pres- 
ence of both diseases. Cultures were made from the gall 
bladders in seven cases at operation with the following 
results: 

Streptococcus hemolyticus in 2, 


Staphylococcus albus (hemolytic) in 2, 
Stapholococcus albus (non-hemolytic) in 1. 


The observers suggest the possibility that such cases 
represent a group of anemias caused by bacterial alter- 
ation of the cholesterol of the cystic bile. Percy, who has 
cultured 7 gall bladders removed at operation in cases of 
pernicious anemia, obtained organisms (hemolytic strep- 
tococcus, B. coli, or streptococcus viridans ) in 4 instances. 

Such cases provide illustrations of superadded septic 
influences, and are not sufficiently common to be con- 
sidered essential to the disease under consideration. 

The epigastric pain is occasionally a prolonged and 
puzzling symptom, with no associated data, excepting 
the achlorhydria, to explain it. When it is associated with 
precordial pain, one may be tempted to regard it as of 
cardiac origin. At other times it may be referred from 
the spinal cord and be of the same nature, though of less 
degree, as the exceptional girdle pain and lightning 
pains noted in this disease. In such instances of posterior 
column degeneration, abdominal crises may occur and 
patients have suffered from fruitless laparotomy under 
these circumstances. 

Diarrhoea may characterize certain cases. The word is 
not used in this connection to signify a transient loose- 
ness of the bowels or a seasonal attack of dysentery, but 
to indicate a phenomenon, debilitating and intractable, 
extending over months and even years. Few normal per- 
sons, if any, and few patients with other diseases can 


102 PERNICIOUS ANEMIA 


recall comparable diarrhoea. They may not volunteer 
the information. Sometimes it occurred so long ago (even 
20 years since) that they fail to associate it in any way 
with their present condition, but recall it vividly when 
reminded. It may have been a matter of five stools a day 
over a period of two months, or of five stools a day for 
six months, or for three months every autumn for three 
years, etc. One patient, a woman of 50, had an attack 
lasting eight months in England, 12 years before develop- 
ing the disease in Canada, and a second attack 2 years 
previous to the disease, lasting one year. During each at- 
tack she vomited a good deal, and each attack gave place 
to obstinate constipation. Another patient, a woman of 
39, had spent her first married winter, at the age of 20, 
day and night, mostly on the shovelled path to the out- 
house. The most striking example among the writer’s 
patients, was that of a farmer, aged 56, treated for two 
and a half years for “tuberculosis of the intestines’, who 
during this entire period, averaged 10 stools a day and 
became reduced markedly in weight and incapacitated for 
his work. While waiting for a shave in the barber-shop he 
found it necessary to absent himself so frequently that he 
was playfully accused of going to the lavatory to tipple 
from a supposed flask of whisky. Suddenly the diarrhoea 
ceased and gave way to constipation. Two weeks later 
while feeding a threshing machine he noticed marked 
tingling and numbness in his right arm. Within a month 
he was a definite case of subacute combined degeneration 
of the spinal cord, although even after a period of two 
years since the diagnosis he has never shown any anemia, 
simple or specific. 

In some cases, diarrhoea takes the form of a constant 
looseness of the bowels, with several stools per day, pain- 
less but urgent. 

The symptom is usually to be distinguished from the 
diarrhoea of sprue by not showing the same matitutinal 


THE DIGESTIVE SYSTEM 103 


occurrence but by being spread out over the entire waking 
hours, and by the stools possessing a less fermentative 
character. The stools may vary in color from greenish to 
brown, and, on standing, the outer portion turns darker 
owing to the oxidation of the blood-derived pigment con- 
tained in them. Gross evidence of indigestion may be 
noted in the particles of vegetable and animal fibre passed. 
Not infrequently mucus, blood, and pus may be detected 
microscopically or occult blood may be demonstrated. 
Frank colitis of a mucous character may dominate the 
picture. In some instances, great rectal discomfort and a 
sense of local burning may precede the act of defecation. 

Diarrhoea in some form occurs in 20 to 25 per cent 
of cases either before or during the disease. Its cause is 
not clear. It resembles in all respects, even to the inflam- 
matory character of the stools, the diarrhoea seen so often 
in achlorhydria without pernicious anemia. It is impos- 
sible to regard achlorhydria as an imperative cause of 
such a symptom since it may be entirely absent both in 
pernicious anemia and in uncomplicated achlorhydria. 
Cabot is said to regard the diarrhoea as of benefit to the 
patient. Many practitioners have given up the attempt to 
check it. Purgation, which causes a temporary diarrhoea, 
sometimes is followed by a slight improvement in a pa- 
tient’s feelings. Few patients who have commenced colon 
irrigations wish to discontinue them. Purgation by drugs 
or by diet has formed a prominent factor in most of the 
many “cures”’. 


ANATOMICAL AND HISTOLOGICAL CHANGES OTHER THAN 
THOSE OF THE TONGUE 
Stenosis of the oesophagus has been reported at au- 
topsy. 
Fenwick (199) in 1870 demonstrated a well-marked 
and extensive atrophy of the secretory tubules of the 
stomach. He found no evidences of chronic inflamma- 


104 PERNICIOUS ANEMIA 


tion, but noted fatty transformation of the glands. He 
considered the atrophy the result of a slow degenerative 
process and the essential cause of the disease, for in cases 
where it could be observed, digestion of food would pre- 
sumably be so interfered with that a general starvation 
of the tissues would result. Flint (205) concluded that 
some cases of severe idiopathic anemia depended upon 
degenerative atrophy of the gastric glands. Schauman 
(553) observed in a true case of pernicious anemia a 
virtual absence of stomach epithelium, the remaining 
glands being few and badly developed, while the whole 
tissue was characterized not only by fibrous tissue in- 
crease but by small subepithelial hemorrhages. In one 
case, Quincke (510) found the mucosa of the stomach 
very thin and the glands few in number, and in a second 
case, a diphtheritic colitis. Bramwell noted slight intes- 
tinal ulceration. Eichhorst (165) felt that any changes 
found were due to the anemia and of little consequence. 
However, in one of his cases the mucosa of the intestine, 
the upper part of the jejunum, the lower part of the ileum, 
and all the colon were edematous with small hemorrhages 
on the edges of the villi. Nolan (474) from a study of 
two cases believed the glandular degeneration to be the 
real cause of the anemia. Nothnagel claimed to show intes- 
tinal atrophy in 84 per cent of his corpses. Pye-Smith 
(507), in an analysis of 103 cases in 1883, noted the fre- 
quent occurrence of fatty degeneration of the gastric 
glands, occasional leucocytic infiltration between the 
tubules, anda thickening of the mucosa with parenchyma- 
tous atrophy. Henry and Osler’s (265) case showed 
atrophy of the gastric mucosa with complete destruction 
of the peptic glands over the greater part. Toward the 
pylorus, atrophy was less marked, but a small-celled 
infiltration, denoting a chronic interstitial inflammation, 
was plainly made out. “A careful study of the case justi- 
fies, we believe, the conclusion that a primary atrophy of 


THE DIGESTIVE SYSTEM 105 


the mucous membrane does occur, and bears out the sug- 
gestion of Flint, Nothnagel and others, that certain of 
the cases of progressive pernicious anemia depend upon 
the profound alteration in the gastric tubules.” They 
mention chronic abuse of alcohol in this case as probably 
a cooperative factor in producing the atrophy. 

Lewy (371) thought the same histological picture re- 
sulted from ulcerative processes, responsible for the hem- 
atemesis in his case. In Kinnicutt’s (377) first case t1- 
bules were absent over large areas, while elsewhere tu- 
bular fatty degeneration, hyaline change, small-celled in- 
filtration were noted, although there was no fibrosis and 
the submucous coat appeared normal. In his second case 
the greatest destruction occurred in the deeper portion of 
the tubules, and was probably caused by a chronic inflam- 
matory process. He could not conceive of these changes as 
being due to a creeping ulceration. Some cases of perni- 
cious anemia might, in his opinion, be due to the impaired 
nutrition resulting from consequent functional debility 
of the stomach. 

Rosenheim (536) noted cystic degeneration of the mu- 
cosa as well as other evidences of catarrhal inflammation. 
Hale-White (249), in an analysis of the gross anatomical 
features in 17 cases from Guy’s Hospital post-mortem 
records, noted in 6 cases certain abnormalities. In the 
first case,—caecum edematous, two blackish small spots 
on the mucous membrane, almost diphtheritic in appear- 
ance; in the second—numerous ulcer cicatrices in the 
large intestine, or newly-healed ulcers, and a little recent 
diphtheritic inflammatory exudation in parts ; in the third, 
—thickening of the pyloric mucosa; in the fourth,—the 
scar of a small healed ulcer one foot above the caecum; 
in the fiith—a few follicular ulcers in the colon; in the 
sixth—several scars in the lower part of the small 
intestine. 


106 PERNICIOUS ANEMIA 


Mott’s (456) case showed no definite microscopic 
changes in the stomach wall, although he noted that the 
mucous membrane was covered by a thick layer of glary 
mucus. Eisenlohr (167) noted in his case not only gastric 
atrophy but also a complete disappearance of glands and 
vuli in the intestine. He felt strongly that nutritional dis- 
turbances consequent on this extensive atrophy caused 
the disease, and furthermore that the process was one of 
primary, genuine atrophy. Nonne (472) found evidence 
of chronic inflammation both of the mucosa and submu- 
cosa of the stomach but could detect no glandular atrophy. 

Pepper and Stengel (494), as well as Hayem (259), 
noted atrophic changes in the stomach, although in one 
of Hayem’s cases, gastritis without atrophy existed. 
Ewald (179) emphasized the intestinal atrophy in addi- 
tion to the gastric atrophy, as the obvious cause of the 
disease. Martius (406) claimed to have noted pronounced 
atrophy of the intestinal, as well as the gastric mucosa in 
2 of 17 cases, and adopted the view that the intestinal 
changes noted were decidedly the more responsible for 
the disease, and acted by disturbance of food absorption. 

Grawitz (220) found gastric atrophy, in one case mod- 
erate, in another marked, but was non-committal with 
regard to its significance. Koch found atrophy in both the 
stomach and intestine in five cases, thus confirming the 
observations of Ewald and of Martius, but felt that these 
findings were secondary to the anemia. Fletcher (204) 
discovered old inflammatory lesions of the colon, asso- 
ciated with patchy necrosis, hyperemia, and hemorrhages. 
These he regarded as due to neurotrophic disturbances. 

Hunter (292) made similar observations on the occur- 
rence of inflammation and atrophy in the wall of the 
stomach. Some of his descriptions are graphic as, for 
example, the following: 

“.. . IL found post mortem, marked inflammatory le- 
sions, both old and recent, in the mucous membrane of the 


THE DIGESTIVE SYSTEM 107 


stomach. The inflammation was localized and, at certain 
parts, of the most intense description; the changes in the 
glandular cells and the infiltration with leucocytes recall- 
ing at once the similar appearances frequently presented 
by glandular structures, like the kidney, when the seat of 
a localized infection. 

“Furthermore, the swollen, pinkish, translucent appear- 
ance of the small lymphatic glands, lying on the wall 
of the stomach itself,—under ordinary circumstances 
scarcely visible to the naked eye,—pointed to some recent, 
as well as chronic irritation of the stomach wall itself.” 

Hunter’s conception may be briefly summarized as fol- 
lows: the gastric atrophy was the result of a gastritis 
due to septic organisms swallowed from the mouth, but 
the gastric atrophy was neither the cause nor the result 
of the disease. It was to be regarded as an associated con- 
dition. In order to explain the disease, Hunter hypothe- 
sized a specific infection by an unrecognized micro- 
organism for whose successful invasion the septic influ- 
ences had well prepared the tissues. 

As may be surmised from this brief review, the prob- 
lem of the gastro-intestinal pathology was in an unsatis- 
factory state at the close of the last century. Nothnagel, 
Ewald, and Martius all championed intestinal atrophy as 
the cause of nutritional disturbances which underlay the 
disease. It remained for Faber and Bloch (185) to detect 
the fallacy of this argument, by doing away completely 
with the conception of intestinal atrophy. By injecting 
five hundred cubic centimeters of ten per cent formalin 
into the peritoneal cavity immediately after death to pre- 
serve the tissues, they found that no atrophy of the intes- 
tine existed. What had given such an appearance was the 
post-mortem gaseous distention of the bowel. In experi- 
ments with dogs they demonstrated how easily this dis- 
tention might deceive. They showed, moreover, that the 


108 PERNICIOUS ANEMIA 


intestine in pernicious anemia harbored no inflammation 
in its wall. 

This left still unsettled the problem of the constancy of 
atrophy and inflammation in the gastric mucosa. Faber 
and Bloch, again using the technique of formalin fixation, 
showed that while atrophy might or might not exist, 
chronic inflammation (in other words, gastritis) was 
always present. 

The observations of these workers have been confirmed 
by Lepehne (367). No observations on the intestinal his- 
tology should be seriously considered unless the methods 
of Faber and Bloch are employed. Such methods might 
do away with some of the more recent alleged findings of 
intestinal atrophy. Passey (485) has brought the method 
of biopsy to bear on the problem of the stomach condition. 
In one case of true pernicious anemia with achlorhydria, 
a section of the fundus, removed at operation, showed 
the oxyntic cells fewer than normal, very little atrophy 
indeed, but definite evidences of inflammation. This bears 
out the findings of Faber and Bloch, that whether atrophy 
is present or not, inflammation is always to be found. 

The more recent reports on pathological findings in the 
intestine deal largely with strictures, obstructions, and 
hypertrophies of the small bowel and with disease of the 
large bowel. Maynard and Sturton (411) report a case 
of an individual who nine years before the disease had 
suffered from colitis, and at autopsy a fine ring of 
small ulcers was found at a point five feet above the 
ileocaecal valve. The outer surface of the gut at this point 
showed a sharp line just as if an end-to-end anastomosis 
had been performed, although there had been no oper- 
ation. Microscopically, the mucous layer showed simple 
ulceration, while the other layers were normal. This ulcer- 
ated region caused no constriction of any kind whatever. 
Coates reports a case who showed at autopsy definite 


THE) DIGESTIVE SYSTEM 109 


ulcers of the large bowel with a large ileocaecal gland 
draining the area of an ulcerated patch. 

Chapman and Duff (107) in April, 1921, opened the 
abdomen of a patient on account of a diagnosis of intes- 
tinal obstruction. The colon was distended but there was 
no recognizable cause for the obstruction. A colostomy 
was done and the patient remained in perfect health until 
August, 1923, when she returned complaining of dys- 
pnoea, and a diagnosis of pernicious anemia was made. 
They felt that the pernicious anemia was due to the same 
toxemia that had caused the paralytic condition of the 
colon. 

Faber (181) reported the first instance of intestinal 
stenosis with pernicious anemia in 1895. Meulengracht 
(429) has given particular attention to these cases of 
so-called “stricture anemia’. In 1921 he reviewed seven 
cases from his own experience and from the literature. In 
1922 he (432) reported a further instance in a woman 
of sixty-four, with three strictures in a certain segment 
of the small intestine. Haden (248) has reported a case 
of clinically typical pernicious anemia occurring with a 
malignant tumor of the gall bladder and obstruction of 
the duodenum and colon. He considered it probable that 
the toxic agent responsible for the anemia had arisen as 
a result of the stasis or of some alteration in intestinal 
function, induced by the presence and perhaps pressure 
of the tumor. 

Ross (534) attended a physician who developed per- 
nicious anemia soon after swallowing a sharp piece of 
lamb bone. The bone lodged in the wall of the ileum and 
was afterwards passed with the stools, but the patient 
died of pernicious anemia. 

Kleeman (339) reports the finding of simple pyloric 
hypertrophy in pernicious anemia. The case was operated 
upon for a schirrhous growth of the pylorus. Percy (495) 
who has operated upon more cases of pernicious anemia 


110 PERNICIOUS ANEMIA 


than anyone else has done, stated, in reply to a question 
by Gibson, that in seventy-seven laparotomies in this dis- 
ease he had never encountered pyloric stenosis. 

Mayo (413) has noticed the frequent development of a 
severe anemia, sometimes indistinguishable from per- 
nicious anemia, in disease of the colon, particularly of the 
proximal half. 

Whereas a few instances of pernicious anemia show 
various abnormal conditions of the intestine, such as those 
just described, most cases do not present such findings. 
Surgeons will agree that similar abnormalities are fre- 
quently found at laparotomy without any associated pic- 
ture of pernicious anemia. The obvious inference is that 
such abnormalities are not essential but may be contribu- 
tory, in some way, to the development of the disease. 

To sum up,—it is recognized that atrophy of the gas- 
tric mucosa may or may not occur; that gastritis always 
occurs; that intestinal atrophy and infection are not 
proved and much doubted; and that a few cases show 
stricture, ulcer, or neoplasm of the bowel. 


THE FUNCTIONAL STATE OF THE DIGESTIVE SYSTEM 


The ordinary bad state of the teeth, the gastric hyper- 
motility, giving place later to atony, and the fact that 
few patients are free from either diarrhoea or constipa- 
tion, are mechanical considerations that should not pass 
unnoticed. 

No particular study of the salivary secretion has been 
reported. Dry mouth is a common complaint and Hunter 
has observed salivation. 

The reader should refer to Chapter III for a review 
of the present position with regard to the gastric secre- 
tion. It was there emphasized that achlorhydria is prac- 
tically always present, that it precedes the disease, forms 
the obvious link in familial cases, and may be regarded 
as a constitutional dysfunction not dependent on atrophy 
or gastritis. 


THE DIGESTIVE SYSTEM 111 


Kahn and Barsky (331) found abundant pancreatic 
ferments, and protease, amylase, and lipase in normal 
quantities in the duodenal contents and feces in pernicious 
anemia patients. Hurst (307) as well as McClure et al. 
(414) found the pancreatic function normal both as re- 
gards enzyme secretion and alkaline fluid secretion. 
Landau et al. (352) claim to have found pancreatic 
achylia in patients with pernicious anemia. 

Kahn and Barsky found liver function normal except 
that the sulpho-conjugation test showed a deficiency in 
hepatic detoxication. Thus the glycogenic and ureogenic 
functions were normal and Bauer’s galactose test as well 
as Strauss’s levulose test were négative. Arnoldi and 
Schechter (17) have attempted to establish a relationship 
between gastric secretion and the functions of the liver 
and pancreas. 

BACTERIOLOGY 

Panton et al. (482) found only twenty-one cases out of 
one hundred and seventeen in whom the mouth was free 
of sepsis. Out of one hundred and four cases, forty-seven 
showed pyorrhoea, ten had carious teeth, twelve had 
clean teeth, nine had good teeth, and thirteen had false 
teeth. Lloyd (383) has indicated the frequent associ- 
ation, in pernicious anemia, of tonsillar and nasal infec- 
tion with oral sepsis. Oscar B. Hunter (287) noted 
increased numbers of spirillary forms in the saliva. 

Kopeloff (347), from his bacteriological work on the 
stomach contents, showed that the gastric flora was the 
result of the oral flora, transferred by the swallowing of 
food and saliva. It is now agreed that the enterococcus, 
B. coli, and B. welchii are present in the stools in larger 
numbers than in health. B. welchii, however, is present in 
equally large numbers in the stools of cases of uncompli- 
cated achlorhydria. Seyderhelm has indicated an en- 
croachment of the colonic flora upon the ileum. This 
general overgrowth of the small intestinal flora probably 


te PERNICIOUS ANEMIA 


depends on an increased alkalinity of the ileum and 
jejunum, resulting from the lack of free HCl in the stom- 
ach, and cannot be regarded as specific to pernicious 
anemia (Nye, 475). 


PARASITOLOGY 


The following parasites have been found in the stools 
of pernicious anemia,—Balantidium coli (385, 323), 
Ankylostomum, Ascaris lumbricoides (567), Strongy- 
loides intestinalis (487), Taenia solium (145), Tricho- 
monas intestinalis and Monilia pisilosis (661). Whether 
these organisms are incidental findings or whether they 
may at times cooperate in producing the disease is a ques- 
tion quite unsettled. Where Dibothriocephalus latus is 
found, it may be considered the cause of the anemia, 
which is not true pernicious anemia. 


CHAPTER VI 
THE BLOOD SYSTEM 


The anemia, as betrayed by pallor and weakness, is 
clinically, and was historically, the most striking feature 
of the disease and directed almost all the early inquiry 
toward the blood system. Pernicious anemia came upon 
the medical public, through Addison’s description, at a 
time when leukemia was much in its mind, owing to the 
publications of Bennett and of Virchow. One of the first 
questions arising was whether any relationship existed 
between the two, particularly whether any increase of 
leukocytes occurred in “idiopathic anemia.” 

Some of the names then used to designate the more 
obvious cellular changes in pernicious anemia have been 
retained for general hematological description. The early 
studies of the blood and bone-marrow in this disease defi- 
nitely stimulated the normal studies of these tissues, which 
have resulted in the complex and controversial findings 
of the blood anatomists. 

During the seventy-five years of histological blood 
investigation on pernicious anemia the names of Pepper, 
Cohnheim, Quincke, Neumann, Osler and Gardner, 
Eichhorst, Laache, Ehrlich, Muir, Askanazy, Pappen- 
heim, Hunter, and more recently of Bunting, Brown and 
Peabody, and G. R. Minot require special notice. The 
time-honored arguments on the relative importance of 
blood destruction, blood production, and disturbed form- 
ation can scarcely be said to be settled. On the other hand, 
the characteristics of the blood picture are well known, 
and the histology of the fixed tissues has become familiar 
to students in general. 


[ 113 ] 


114 PERNICIOUS ANEMIA 


SYMPTOMS AND SIGNS ARISING FROM CHANGES IN 
THE BLOOD SYSTEM 

The alterations in this system are responsible for the 
weakness of the patients, their color, and probably for 
the occasional enlargement of the spleen and liver. 

W cakness is a cardinal symptom in pernicious anemia, 
and constitutes the chief or only complaint in the majority 
of patients when first seen. It is usually accompanied by 
dyspnoea on exertion although some patients show a 
remarkable degree of adjustment to lack of respiratory 
pigment. Dizziness, defects of memory, lack of concentra- 
tion, melancholic moods, and headache may be attributed 
in some degree to mild trophic or oxygenation distur- 
bances of the cerebrum or meninges, depending on the 
anemia. The weakness is usually so gradual in its onset 
that at first it is not subjectively remarked. Ultimately 
a blood level is reached at which the customary energy 
demands are not met and fatigue becomes evident. 
When first seen complaining of weakness, the patient has 
red blood cells usually numbering two million per cubic 
millimeter or slightly more. It is possible to estimate, from 
a comparison of the few cases in which the blood has been 
followed from the beginning of the anemia, that these 
patients who come first on account of weakness have had 
anemia developing over a period of from two months to 
a year. No estimate can apply in all cases, since the rap- 
idity of the development of anemia varies in different 
cases, but it is certain that where weakness is the initial 
complaint anemia has already been present for some 
months. 

Most patients exhibit a lemon- or grapefruit-tinted 
pallor; a few, merely a pallor, wax-like and intense; a 
small group are definitely jaundiced. In uncomplicated 
cord involvement, the complexion is of a muddy gray 
color. The sclerotics, during phases of rapidly developing 


fae BEOOD SYSTEM 10S 


anemia, are usually bile-stained. Patients who have taken 
arsenic in large doses over a long period usually show 
some pigmentation of the exposed skin areas. The appear- 
ance of the patient is due to the anemia, to the staining of 
the skin and sclera with bile-pigment, and to the tendency 
to preservation of the subcutaneous fat. The lips are pale 
and, if not too pale, somewhat cyanosed. In spite of the 
pallor of the face, there ordinarily remains, over the 
cheeks, a ‘slight suggestion of pink. Duke and Stafer 
(157) showed that capillary blood counts were 17.6 per 
cent higher than simultaneous venous blood counts, owing 
to the lagging of macrocytes in the narrow capillary beds 
where the blood flow is slow and the pulse absent. This 
no doubt explains the suggestion of color in even these 
patients with marked anemia. It is said that pernicious 
anemia patients freckle or sunburn very readily. Leuko- 
derma and bronzing have been occasionally noted, but do 
not constitute essential features of the disease. 

The spleen and liver, not infrequently enlarged, are so 
unavoidably to be thought of in connection with the 
destruction of blood,sthat their enlargements may be asso- 
ciated tentatively, at least, with the blood state. 

Blood abnormality occurs in ninety per cent of all cases 
diagnosable as pernicious anemia. The blood system there- 
fore occupies a middle position between the digestive and 
nervous systems, the former of which is abnormal in one 
hundred per cent, and the latter in eighty-four per cent 
of all cases. 

Distinct emphasis should be laid upon the fact that 
changes in the blood, in the majority of cases, precede all 
other symptom-producing changes in any, or all, systems. 
Otherwise expressed, blood changes are usually the 
second abnormality to develop, achlorhydria being the 
first. While such a priority is very usual, it is not obli- 
gatory. Glossitis or nervous change may appear first, as 
has been previously stated. The blood changes may begin 


116 PERNICIOUS ANEMIA 


concurrently with either glossitis or cord degeneration, 
or both. Blood changes, however, are never completely 
absent. Even cases of so-called “pure” subacute combined 
degeneration of the cord, which may continue without 
anemia for years, show anemia of this special type, if at 
no other time, as a terminal event. 

Abortive blood pictures strongly suggestive of perni- 
cious anemia have been seen in the course of other diseases, 
only to clear up and not return. Mayo (413) has noted 
this. Warley (666) had a case in a man of thirty-five, 
with gastric ulcer, who, six weeks after excision of the 
ulcer, was seen in consultation by competent physicians, 
and a diagnosis of pernicious anemia made. Within six 
weeks the anemia entirely disappeared, and his blood has 
been in good condition for three years since then. Rey’s 
(522) case may be another example. 

Terminal blood pictures, strongly suggestive of the dis- 
ease may occur in other conditions, as in that reported by 
Gynn and Abram (214 A) in a case of tuberculosis. In 
this case it is possible from the finding of B. welchii in 
the portal blood that a macrocytic anemia by this organ- 
ism was responsible, and that it was not a true “perni- 
cious” blood picture. The writer saw a puzzling, perni- 
cious-like anemia as a terminal phenomenon, during six 
weeks in a case of auricular fibrillation. 

Piney (499) has emphasized the belief that intercur- 
rent disease occurring during the course of pernicious 
anemia either partly or completely obliterates the typical 
blood picture, and cites Weinberg’s case. Faber (184) as 
well as Squier (587) makes use of this belief to buttress 
the argument that the disease is due to absorption from 
the intestine of foreign protein, such intercurrent dis- 
ease acting as a desentizer, similarly to the parenteral 
injection of foreign protein. 


THE BLOOD SYSTEM OL? 


THE REMISSIONS 


The remissions of pernicious anemia constitute one of 
the most impressive spectacles in the field of medicine. 
They are considered in connection with the blood changes 
because they are chiefly reflected in the blood state. Since 
they give character to the course of the disease and also 
naturally divide the disease into types, these two subjects 
will also receive attention in this connection. 

A remission is a spontaneous blood improvement, 
accompanied by general symptomatic improvement. It is 
more or less unlimited as to its length or brevity and to 
the degree of improvement, is virtually unpredictable, and 
totally unexplainable. 

Remissions are not obligatory, since some cases run 
either acute or chronic courses without improvement. 
The most acute course seen by the writer was that of a 
man of fifty-eight, who died five months after the first 
evidence of blood change had appeared. This is as acute 
as any case reported, but not more so. 

Panton et al. (482) found, in one hundred and three 
patients in whom the point could be determined, that 
eighty-four showed remissions while nineteen did not. 
The course of the disease is longer in those showing 
remissions than in the others. In the above series the 
average length of the illness with remissions was two and 
nine-tenths years, and without remissions eight-tenths 
years. This computation is based on the standard of the 
first symptom as the beginning of the disease. Of one 
hundred and eleven cases seen between 1909 and 1920, 
and subsequently traced, eight were alive at the begin- 
ning of 1923. The average expectancy of life, from the 
first symptom, is roughly two and five-tenths years. 

The number of remissions seen in various cases is from 
one to twelve, although two or three represent a fair 
average. 


118 PERNICIOUS ANEMIA 


Some remissions are so short that the blood peak at- 
tained may be held for only a few days. First remissions 
have an average length of ten months, while subsequent 
ones are characteristically shorter and less satisfactory 
in degree of improvement. 

Relapses vary in length from a few weeks to several 
months, occasionally two years. While long relapses are 
seldom followed by improvement, and therefore consti- 
tute an unfavorable prognostic sign, they are, in excep- 
tional instances, followed by excellent remissions. In one 
of the author’s cases a two-year relapse was followed by 
a four-year remission. 

Long courses of pernicious anemia are due to long 
remissions. Five-year remissions are not so rare as for- 
merly thought. Von Willebrand (627) reports a remis- 
sion of 10 years’ duration, Stockton (600) one of 12 
years, Speidel and Goss (586) one of 14 years, Swan 
(604) of 16 years, McPhedran (423) of 18 years, while 
Hurst (309) has two cases in whom unbroken remis- 
sions have lasted 20 years, one of the latter patients hav- 
ing recently donated blood for transfusion. The question 
of spontaneous cure in the long remissions is an open 
one with the balance of evidence in the negative. So far 
as reported, all these cases die eventually of pernicious 
anemia, although the normal expectancy of life may have 
been realized. 

The blood state during remissions will be described 
later. Briefly, marked increase of red blood cells and 
hemoglobin occurs, the amount of circulating bilirubin 
decreases, the color of the skin improves, and the sclerotics 
become freer of pigment stain. The morphology of the red 
blood cells approaches normal. The rapidity with which 
these improvements occur varies considerably in differ- 
ent cases, and the degree of improvement attained like- 
wise varies. It is exceptional to find either the erythrocyte 
count or the hemoglobin percentage as high as normal. 


Lae BLOOD SYSTEM 119 


Former levels are, nevertheless, occasionally attained in 
long excellent remissions. However long or satisfactory 
the remission may be, the red blood cell morphology very 
seldom becomes normal. Remissions in which the macro- 
cytes entirely disappeared from the blood were phrased 
by Nageli “absolute remissions.” 

(In passing, it should be noted that remissions follow- 
ing the use of liver diet differ in some respects from an 
average spontaneous remission. Normal or even super- 
normal blood levels may be attained and cellular morpho- 
logy usually becomes normal. These points will be con- 
sidered presently in detail.) 

The strength of the patient may return sufficiently 
to enable him to resume his habitual occupation, even 
manual labor, although he is usually either forced to half- 
time employment or suffers greatly from fatigue. But 
many are able for considerable periods of time to do an 
amount of work which, in view of their blood level, is 
surprising. 

Glossitis frequently persists during all but the most 
excellent remissions, and exacerbations of glossitis may 
signal the beginning of a relapse. Dyspepsia usually im- 
proves. 

The spinal cord signs show, at best, an arrest of prog- 
ress. Ataxia or paresis are permanent. Some slight im- 
provement in the parasthesiae or numbness may occur 
and probably results from the small margin of functional 
recoverability possessed by nerve tissue, especially the 
peripheral nerves. Heretofore it has been unusual to see 
a patient in a long remission with quiescent but trouble- 
some ataxia, for the reason that cases with marked cord 
involvement seldom had splendid remissions. The effects 
of liver diet are gradually bringing out this type of pa- 
tient. One patient has worked as a charwoman for two 
years, her blood level above normal, her only disability 
being residual cord change with ataxia. 


120 PERNICIOUS ANEMIA 


The first remission is usually and in all respects better 
than subsequent ones, for in the latter there is the ten- 
dency to less and less blood improvement. The final remis- 
sion may pass almost unnoticed. While this downward 
gradient in successive remissions is the rule, cases are 
seen in which the second or third remission is incompar- 
ably better than the previous one or ones. 

The patient’s health, in the first stages of the disease, 
roughly follows the hemoglobin level, for a remission is 
largely a blood improvement and a relapse is largely a 
blood failure. In arthritis deformans, diabetes, chronic 
nephritis, and asthma, there occur periods of spontaneous 
improvement little remarked because so unspectacular. 
In pernicious anemia the fluctuating symptom is the ane- 
mia, one calculated by its effect on the complexion and 
energy to make the phenomenon obtrusive and spectacu- 
lar in the extreme. Nervous involvement may first begin 
precisely at the peak of a blood remission. The real state 
of the patient, in the last stages, is actually so unrelated 
to the blood condition that death may occur with a blood 
level at which formerly the patient did manual labor. In 
such cases, nervous involvement is marked. 

Nevertheless, even in cases of subacute combined de- 
generation of the cord, long periods up to five years may 
elapse during which the symptoms and signs show no 
progress. 

A remission may begin so gradually that its exact begin- 
ning cannot be determined. In other cases it has been pos- 
sible to name almost the hour when the change occurred. 
At the depth of a relapse patients have been known to 
express a sudden feeling of improvement,—a peculiar 
euphoria and assurance,—which has proved a reliable 
indication of a remission. 

Patients have roused from coma and requested articles 
of food so substantial as to amaze their attendants. One 
such case of Harris McPhedran’s (424) at the Lockwood 


THE BLOOD SYSTEM 121 


Clinic, woke from coma, which had been presumed fatal, 
and asked for ham sandwiches. Within an hour he made 
a second similar request and again ate the sandwiches; 
after a sound sleep he ordered and ate an exceptionally 
hearty breakfast ; three weeks later he was able to travel 
fifty miles to the clinic and was found to be in an excel- 
lent remission. One of Goldie’s (229) cases, after spend- 
ing the night in deep coma from which he could not be 
aroused, awoke in the morning and insisted on having his 
favorite article of diet,—fried potatoes. From that mo- 
ment he rapidly improved and has been in the most per- 
fect remission for a period of fourteen years. 

Goldie has noted severe nasal hemorrhage at the very 
depth of the relapse in each of four cases, conspicuous 
because of the exceptionally long remissions which they 
have since enjoyed. In one case, during what was regard- 
ed as fatal coma, the patient bled approximately a pint 
from the nostril, and, waking in the morning confessed to 
a remarkable euphoria and appetite. He has now been in 
a perfect remission for five years. 

On the basis of the balance maintained between blood 
destruction and blood formation, Archibald (13) and 
Minot and Lee (446) have suggested dividing all cases 
into the following groups: 

(1) Cases of a rather acute nature that progress steadily 
downward to a fatal termination, the blood destruc- 
tion always being in excess of blood formation, and 
never letting up. Such cases are not to be confused 
with acute hemolytic anemia depending upon sepsis, 
or with idiopathic aplastic anemia. 

(2) Cases characterized by marked or fair remissions 
in the course of the disease, occurring quite sharply 
or gradually. There is usually considerable blood 
destruction during relapses and little during remis- 
sions ; blood destruction may be absent during remis- 
sions. 


122 PERNICIOUS ANEMIA 


(3) Cases that show persistently a considerable degree 
of blood destruction with relatively slow, never very 
striking, remissions, but which do not have serious 
relapses, except after years or terminally. These 
cases approach the condition of acquired hemolytic 
jaundice. 

(4) Cases of a chronic nature that slowly progress down- 
ward though interrupted by mild remissions and 
rarely by moderate remissions. This type merges 
directly into the next. 

(5) Cases of a continuous chronic nature that very slow- 
ly progress downward with usually no or only very 
slight remissions and with a sluggish, inactive mar- 
row. 

Chosroeff (114) made a similar, though much less 
satisfactory, division into the following groups, (1) 
chronic intermittent, (2) acute form, (3) aplastic form. 

The above division into five groups, upon the basis of 
the course of the disease, is the only justifiable separation 
of cases into various types. 


ANATOMICAL AND HISTOLOGICAL CHANGES 

Neumann’s (468) discovery of nucleated red corpuscles 
in the bone-marrow in a case of severe simple anemia 
marked the beginning of hematology (1868). Immerman 
(314) noted the reduction in the number of red corpuscles 
in pernicious anemia and thought this explained the fever. 
He felt justified in dividing the disease into a primary 
form, severe from the beginning, and a secondary form, 
in which the severe characters were added to an existing 
simple anemia. 

Pepper (493), the first to describe the bone-marrow, 
regarded the changes as a hyperplasia with so conspicu- 
ous a production of lymphoid cells that the disease could 
be classed as a pseudo-leukemia. Cohnheim (123) noted, 
in the shafts of the long bones, a disappearance of the 


THe; BLOOD SYSTEM 123 


fat and an extension of the red marrow to take its place. 
Microscopically he found nests of nucleated red corpus- 
cles, oversized erythrocytes in large numbers, and an in- 
crease of the marrow cells. To him it was a picture of an 
embryonic type of blood formation, brought about by a 
reversion from the adult type and the cause of the anemia. 

Quincke (509) described the great differences in the 
size of the circulating erythrocytes and particularly the 
bizarre shapes of many of them, applying to this latter 
phenomenon, for the first time, the term poikilocytosis. 
He considered the peculiar features of the blood, as com- 
pared with simple anemias, a result of its greater inten- 
sity. 

Neumann (469) confirmed the bone-marrow findings 
of Cohnheim, but considered them the result of a severe 
compensatory effort to overcome the anemia and there- 
fore not of specific importance. Eisenlohn (167) pointed 
out, additionally, very small microcytes in the marrow as 
well as large and small “corpuscle-holding cells” (phago- 
cytic cells), but having found similar marrow changes in 
a case of gastric cancer he concluded that carcinoma of 
the stomach might be one of the many causes of perni- 
cious anemia. 

Osler and Gardner (480) described a case in which 
3 or 4 phagocytic cells, each containing 5 or 6 red corpus- 
cles, were found in a single microscopic field of the verte- 
bral bone-marrow. 

Ehrlich (161) commented upon the fact that the liter- 
ature had previously contained but two cases of pernici- 
ous anemia showing nucleated red corpuscles in the blood 
during life. By his own staining methods he had then 
(1880) found them in all forms of severe anemia, irre- 
spective of the etiology, and described three forms,—nor- 
moblasts, of the size of red blood cells; megaloblasts, pre- 
cursors of the very large red blood cells; and microblasts, 
which were very small and rare forms. 


124 PERNICIOUS ANEMIA 


Riess (524), in five out of seven cases, confirmed the 
finding of phagocytic cells in the marrow and regarded 
this as evidence of blood destruction in this tissue. Litten 
(379), in reply to Riess, stated that he had found such 
“corpuscle-holding cells” in many various diseases and 
did not regard them as distinctive of pernicious anemia. 
Mullendorff (458) confirmed their presence in two cases 
of pernicious anemia. Osler (479), in a study of the 
marrow in seventy-five cases of other diseases, frequent- 
ly found these phagocytic cells, especially numerous in 
tuberculosis, pneumonia, typhoid fever, and ulcerative 
endocarditis, and could not regard them as specific to 
pernicious anemia. 

Hayem (258) described megaloblasts under the name 
of nucleated giant corpuscles. Pye-Smith (507), thor- 
oughly committed to the strict conception of this disease 
as inviolately idiopathic, suggested that cases showing 
such marrow changes as had been described, were of a 
different nature and should be separated from the crypto- 
genic group. 

Grawitz (219) described the blood picture of perni- 
cious anemia occurring in two cases of sarcoma of the 
bone-marrow. Ehrlich (162) described degenerative 
changes in the red corpuscles, some of which we have 
come to regard as signs of regeneration. 

Geelmuyden (221) found that the marrow in perni- 
cious anemia contained many more nucleated red blood 
cells and pigment-holding cells than in health, and that the 
replacement of fatty marrow by lymphoid tissue, fre- 
quently seen in pernicious anemia, occurred likewise in 
other diseases. 

Fagge (190) regarded the marrow changes as second- 
ary and compensatory to the anemia. Litten and Orth 
(380) experimentally produced what they considered a 
comparable marrow by hemorrhage. 


THE BEOOD SYSTEM 125 


Ehrlich (163) stated his belief that the bone-marrow 
was responsible for the anemia because embryonic types 
of cells were found in this tissue and because the granular 
leukocytes, products of the marrow, were numerically 
reduced. To him the appearance in the blood of these 
embryonic cells—the megaloblasts—was a sure sign of 
the ‘“‘pernicious” nature of the anemia. 

Hunter (292), reposing in the idea that compensatory 
hyperplasia explained the marrow findings, unquestion- 
ably did much to belittle the factor of faulty blood form- 
ation which the work of Ehrlich clearly revealed. 

Mott (456), from a study of three cases, while willing 
to admit a reversal of marrow to an embryonic type 
of blood formation, regarded the reversal as, purely 
compensatory. 

Rindfleisch (528) was overwhelmingly persuaded that 
the marrow betrayed a diseased condition by its megalo- 
blastic content, a feature not to be duplicated by mere 
physiological overactivity. 

Howell (279) fully described megaloblasts under the 
name of ancestral cells. Muller (460) was able, from 
embryological studies, to identify with the megaloblasts 
both the nucleated giant corpuscles of Hayem and the 
ancestral cells of Howell, and to show that these cells cor- 
responded with those found in the embryo. He believed 
that just as leukemia was a proliferation of the leuko- 
cytes, sO pernicious anemia was a hyperplasia of the red 
corpuscles. He cast out as hypothetical the idea of a toxin 
in the plasma and completely ignored the conception of 
hemolysis. To him, pernicious anemia was a primary dis- 
ease of the bone-marrow, the essential feature being the 
reappearance of embryonic cells, by which the cachexia 
was produced and the area available for normal blood 
formation was reduced. 

Muir (457) considered that the extension of the red 
marrow with the occurrence of many nucleated forms of 


126 PERNICIOUS ANEMIA 


erythrocytes indicated, above all else, an increased re- 
generative activity. He noted that the most advanced 
changes in the marrow occurred in those cases in which 
the liver was most heavily siderosed. He noted the abnor- 
mal maturation of the megaloblasts but thought the 
embryonal reversion resulted merely from prolonged 
functional strain. 

Askanazy (21) claimed a lineal descent of normo- 
blasts from megaloblasts, the latter being merely the older 
forms. The basic staining of the megaloblasts was really 
a sign of youth, since it was constantly to be noted in the 
young red corpuscles of birds and reptiles and always 
absent from older animals. Contrary therefore to Ehrlich, 
polychromatophilia in the bone-marrow indicated regen- 
erative activity and not a cellular degeneration. 

Pappenheim (483) showed that the breaking up and 
disappearance of the nucleus within the cell body was not, 
as Ehrlich presumed, an evidence of degeneration, but in 
reality the normal process of blood cell maturation. The 
normoblast and megaloblast were not fundamentally dif- 
ferent, for all stages of transition could be traced between 
them. Moreover, great size and staining variations 
occurred among the nuclei both of the normoblasts and 
megaloblasts. 

Both Lazarus (354) and Klein (342) described baso- 
philic granules in red corpuscles. 

Engel (172) made necessary discriminations. Perni- 
cious anemia blood was a reversion not so much to a later 
embryonic type as to an early embryonic type; and, 
since he had found megaloblasts in the blood in severe 
infantine anemias, and Hammerschlag had found them 
in several cases of chlorosis, they were not pathogno- 
monic of pernicious anemia, but denoted rather the action 
of chemical products on the bone-marrow. Ehrlich and 
Lazarus (164) refuted Pappenheim’s contention as not 
being in accordance with clinical facts. Pappenheim’s 


THE BLOOD SYSTEM 127 


(484) valuable paper of 1901 made it clear that the ab- 
sence of megaloblasts from the blood did not mean that 
the case was not pernicious anemia. He also pointed out 
that some anemias with normoblastic blood formation 
could be fatal, and others with megaloblastic blood form- 
ation (e.g., dibothriocephalus) were sometimes curable. 
Hence the term “pernicious” could not be identified 
with a particular type of blood formation. 

Warthin (636) subscribed to the idea that the marrow 
changes were compensatory to blood destruction and he 
demonstrated, for the first time, that increased phagocy- 
tosis of red corpuscles occurred in the hemolymph glands. 

Gulland and Goodall (240), after a careful study of the 
pathology in seventeen cases, felt that the marrow 
changes—‘“‘undue activity of the red cell and white cell 
formation”—were fundamental and causal and were pro- 
duced by the action of heterogeneous toxins. 

Bunting (82) confirmed the work of Pappenheim and 
of Engel on the occurrence of megaloblasts in normal 
marrows of animals and man, and he showed that a differ- 
ence existed between the marrow reaction to bleeding and 
to the injection of myelotoxic serum, hemolytic serum, 
and the poison, ricin. The chief difference may be 
described as follows,—whereas bleeding produced a 
moderate and transient appearance in the circulation of 
normoblasts, the injections produced a much greater and 
much more lasting appearance not only of normoblasts 
but of megaloblasts. By injecting these sera or ricin in 
small amounts frequently over a prolonged period, aniso- 
cytosis and poikilocytosis were produced, and the blood 
picture as a whole bore a striking resemblance to that of 
pernicious anemia. Bunting concluded that a circulatory 
hemotoxic poison affected not only the mature circulating 
erythrocytes but directly the bone-marrow cells. He be- 
lieved that some analogous toxin might be at work in 
pernicious anemia. By such an hypothesis, and by anal- 


128 PERNICIOUS ANEMIA 


ogy with his ricin intoxication experiments in rabbits 
and dogs, he could explain as less severe those cases of 
pernicious anemia with more normoblasts in the blood 
and as more severe those cases with more megaloblasts in 
the blood. The so-called reversion of the marrow to the 
embryonic type became thus understandable and depended 
on a toxic destruction in situ of the maturer red cor- 
puscles, with a delivery of ill-developed young forms to 
the circulation. While no evidence of a toxin in pernicious 
anemia has yet been produced, this classical work of 
Bunting is one of the best arguments in favor of such 
an hypothesis. 

It will be evident that within this historical period, the 
main morphological features of the blood and bone-mar- 
row were described and variously interpreted. Further 
outstanding contributions will be mentioned in the fol- 
lowing pages. 

A.—The fixed tissues. The bone-marrow, spleen, liver, 
and hemolymph glands are concerned, in health as well as 
in disease, both with blood formation and blood destruc- 
tion. In the normal human adult, the bone-marrow is the 
only considerable erythropoietic tissue, and, in pernicious 
anemia, there is but little evidence of any resumption of 
blood formation by the extra-medullary tissues active in 
the embryo. Increased work in pernicious anemia is ac- 
complished by extension of the erythroblastic marrow 
within the bones. The spleen, liver and hemolymph nodes 
greatly increase their normal but moderate function of 
corpuscular destruction, by virtue of the clasmatocytes in 
their reticulo-endothelial tissues. These organs will 
presently require consideration in connection with the 
functional state of the blood system and the perverted 
metabolism of the iron and blood-derived pigments. His- 
tologically the spleen, liver and hemolymph glands present 
a picture chiefly of blood destruction, while the marrow 
presents a double picture,—of destruction, on the one 


THE BLOOD SYSTEM 129 


hand, and of increased and abnormal formation on the 
other hand. 

The bone-marrow was described by Pepper (493) in 
the following words: “Marrow from the canal of radius 
appeared decidedly paler than in health; examined in 
fresh condition, it was found to be made up almost en- 
tirely of granular cells, round or nearly so, but varying in 
size from a diameter of 1-3500 to 1-2000 of an inch. 
Many of the larger of these cells exhibited a single dis- 
tinct spherical nucleus without the aid of reagents” 
(acetic acid). “Marrow from sternum quite red; very 
little oil; made up of crowded cells roundish and granu- 
lar ; on treatrnent with acetic acid, showing in most cases 
a single round faintly granular nucleus; the cells varying 
in size from less than a white blood cell to twice that size, 
the smaller ones preponderating.” 

Cohnheim’s (123) description was, in part, as follows: 
“So much the more astonishing were the marrow find- 
ings. For in all the bones, not only the vertebrae, sternum, 
and ribs, but also all the long bones, the marrow was in- 
tensely red in the diaphyses as well as the epiphyses and, 
moreover, without hemorrhages. Under microscopic ex- 
amination there was a corresponding absence of fat cells. 
Instead were found (1) colorless, so-called marrow cells, 
varying in size, many quite like lymph-cells, but very 
many relatively large with one or sometimes two large 
phlyctenular nuclei of epitheleoid constitution ; quite rarely 
also giant cells with several nuclei, and still more rarely, 
a marrow cell containing blood corpuscles. (2) At least 
in similar quantity, pigmented elements. Of these the 
usual bi-concave red discs formed the decided minority. 
More considerable was the number of globular, red non- 
nucleated cells of different dimensions, the smallest of the 
diameter of normal red cells, the largest more than double 
that of the unpigmented cells, and between these limits, 
every size. But most striking at first look into the micro- 


130 PERNICIOUS ANEMIA 


scope and most common were the red nucleated cells 
varying in size, but the majority resembling the smaller 
epitheleoid marrow-cells. . . . I was particularly struck 
by the flexibility and elasticity of the larger cells which 
would draw out to a point at times if they were pressed 
between others on a slide, or wedged in, until, on being 
free again, they resumed their old form.” 

Osler and Gardner’s (480) description was as follows: 
“The marrow (of the sternum, ribs, clavicle, fibula and 
vertebrae) has a dark, violet-red color, is thick, some- 
thing of the consistency of spleen-parenchyma in fever. 
It contains: (1) Colorless corpuscles (marrow-cells) of 
various form, with granular protoplasm and distinct ve- 
sicular nuclei. Most of them are larger than the white cells 
and have usually only one nucleus. Besides, there are 
many small round elements like lymph cells. (2) Red cells 
of two sorts: (a) the usual bi-concave, somewhat irregu- 
lar-shaped discs, and many with long processes, as also 
observed during life. These form the great bulk. (b) 
Small round non-nucleated cells about 1-4 to 1-2 the usual 
size, similar to those seen in the blood. They are very 
numerous in the fibula where they form a good 1-4 of the 
colored elements. (3) Nucleated red cells (Neumann’s 
transition forms) are numerous in the sternum and ribs; 
in other bones mentioned they are very scarce or else, on 
account of the pallor of the red cells, too difficult to find. 
Generally they are larger than the usual red cells, but 
show like them a very uniformly colored stroma with a 
finely granulated nucleus. They exhibit round, not bi- 
concave discs, often with irregular outlines or one sharp 
process. Their staining is usually just as deep as the ordi- 
nary red cell, sometimes deeper or paler. The nuclei are 
round or elliptical and occupy 1-4 to 1-2 of the cell’s 
volume. They are solid granular and appear stained in the 
cells. Not one nucleolus could be seen. The position of the 
nucleus in the cell was varied but soon after death it ap- 


THE, BEOOD SYSTEM 131 


peared centrally anchored. In the tests on the following 
days, on the contrary, many nuclei lay on the margin 
(peripherally) and others had passed out of the cells and 
seemed now quite unpigmented. . . . (4) Blood-corpus- 
cle-holding cells very plentiful in the vertebral marrow, 
where in one field 3 or 4 appeared each holding 5 to 6 
red cells with plainly preserved pigment and definite 
shape. They are rare in the sternum and ribs and quite 
lacking in fibula and clavicle. (5) Of giant-cells (myelo- 
plaxes of Robin) 1 or 2 were found in the sternum and 
ribs. (6) Fat cells in the clavicular marrow, not elsewhere 
(i.e., in sternum, ribs or vertebrae). (7) Everywhere in 
the marrow 12-30 hours after death, Charcot’s octahe- 
dral crystals were to be found.” 

Gulland and Goodall’s (240) summary was as follows: 
“Tn all cases the marrow was hypertrophied and dark red 
as seen with the naked eye. In every case, however, we 
found a smaller proportion of red cells or, perhaps more 
correctly, a larger proportion of white cells than might 
have been expected. Thus, in only six of the seventeen 
cases, red cells preponderated; in five, myelocytes; in five, 
lymphocytes; while in one case lymphocytes and myelo- 
cytes were present in equal numbers, and together were 
the most numerous elements seen. 

“In every case there was marked evidence of blood 
destruction, as shown by red and white cells which had 
been ingested by large phagocytes and, in seven of the 
cases, pigment showing the free iron reaction was pres- 
ent. Giant cells were found in all cases but were seldom 
normal. They were usually small and degenerated. Eosin- 
ophile cells were very numerous, except in two cases. 
Basophile cells, some of which had the large granules 
noticed in the spleen and intestine, were seen in three 
cases.” 

While marked erythroblastic activity with extension of 
the red marrow is a point upon which all may agree, this 


i392 PERNICIOUS ANEMIA 


phenomenon does not usually, if ever, affect all the bone- 
marrow of the individual. In the cases of Archibald (14) 
and of Tidy (612) certain portions of some of the long 
bones, e.g., femur, tibia, and ulna showed complete aplasia, 
although the marrow of the other bones in each case 
proved erythroblastic. Arthur Sheard (576) found in 
each of two cases, that the bone-marrow had not under- 
gone uniform hyperplasia throughout. In certain portions 
of the long bones, notably the greater part of the tibia, the 
lower portion of the shaft and both extremities of the 
femur and humerus, and also the lower half of the radius, 
the marrow had failed to react to any appreciable degree. 
In the second case, limited areas of these parts were defi- 
nitely aplastic. The color of these portions of fatty mar- 
row was light yellow and not the bright canary yellow 
which characterizes the fat in other parts of the body. 
These findings suggest, as Sheard remarks, that in many 
more cases of pernicious anemia than has heretofore been 
supposed, the erythroblastic reaction of the bone-marrow 
does not occur in a uniform manner throughout the bones 
of the whole body. 

A further point regarding the distribution of the eryth- 
roblastic portions of bone-marrow is of interest. It has 
been shown in the normal adult that the red cellular mar- 
row of the humerus and femur is confined to a small area 
at the upper end (diaphysis) of each bone, while the 
whole radius, ulna, tibia and fibula are filled with fat. The 
surprising feature in Sheard’s two cases was the absence 
of erythroblastic reaction in those portions of the humerus 
and femur which normally should contain some amount 
of erythropoietic activity, and the presence of such reac- 
tion in the greater parts of the shafts of these bones, 
which normally contain little or no demonstrable cellular 
tissue. 

In any given bone, therefore, the condition found may 
be complete aplasia, complete erythroblastic activity, or 


THE BLOOD SYSTEM 133 


distinct areas of both conditions. There is another type of 
marrow sometimes seen,—segregated foci of red-mar- 
row ona generally aplastic field. 

The marrow extends at the expense of the fat and even 
the bone trabeculae until it occupies all or some portion of 
the shaft. The fat and bone are removed by a process of 
softening and simple atrophy, not by the activity of osteo- 
clasts or leukocytes. Active marrow is of a dull red or 
chocolate color. 

Histological sections or stained smears show a confus- 
ing aggregation of various types of cells among which 
are to be distinguished red corpuscles in various stages 
of development, white corpuscles in various stages of 
development, phagocytic cells, and giant cells. 

The definitive erythrocytes show all the abnormalities 
of size and shape that they exhibit in the circulation blood 
—macrocytes, microcytes, poikilocytes. Among the nucle- 
ated red corpuscles may be distinguished examples of all 
the developmental stages,—(1) megaloblasts or parent 
cells, larger than any erythrocytes found, may reach 
twenty w in diameter, and consist of basophilic cyto- 
plasm with a large reticular nucleus usually placed cen- 
trally ; especially large megaloblasts are sometimes termed 
gigantoblasts. (2) Erythroblasts are smaller but similar 
in appearance to the megaloblasts, and are paralleled in 
size by some of the larger macrocytes. (3) Normoblasts, 
somewhat larger than normal erythrocytes, have cyto- 
plasm taking either the acid or basic stain, and nuclei, 
central or eccentric, which have lost the reticular char- 
acter and become pyknotic. The relative numbers of non- 
nucleated and nucleated red corpuscles varies greatly in 
different marrow specimens. Among the nucleated types, 
some specimens show a preponderance of normoblasts, 
others of megaloblasts, When megaloblasts and the larger 
erythroblasts dominate, it usually is in a case which gives 
evidence otherwise of an acute or severe course, and these 


134 PERNICIOUS ANEMIA 


cells represent a physiological dislocation bringing the 
marrow nearer to the early embryonic type. Preponder- 
ance of normoblasts indicates less severe stress, the 
marrow not having been forced to the limit of its embar- 
rassment. The presence of nuclear remains within the 
cytoplasm, revealed by vital staining within the macro- 
cytes, is taken as evidence of abnormal maturation of the 
nucleated predecessors. Thus, reticulum, Cabot ring 
bodies, Howell-Jolly bodies, stippling, extruded nuclei, 
and polychromatophilic cytoplasm indicate prematurity 
and physiological disability, resulting in part from the 
necessity of short-cuts from the normal, more orderly 
type of development. 

The white corpuscles, especially the myeloblasts and 
myelocytes, and also cells of the lymphoid series, show, in 
the marrow, decided leukoblastic activity. Sometimes the 
granular series, sometimes the lymphoid series predomi- 
nates, the one over the other. Eosinophilic cells are, as a 
rule, rather uncommon. This mysterious activity of the 
white corpuscles has been a confusing factor, not only by 
obscuring observation of the red corpuscles, but in the 
earlier studies, by suggesting a relationship to the leuke- 
mias. A distinct parallelism exists between the behavior 
of the red corpuscles and the granular white corpuscles, 
viz., that in spite of this narrow evidence of hyperactivity, 
fewer cells of both kinds are delivered into the blood; and 
again, it is precisely at the same time—during blast 
crises—that the primitive cells of both series appear in 
largest numbers in the circulation. 

Phagocytosis of corpuscles by the clasmatocytes of the 
reticulo-endothelial system of the marrow has received 
fresh investigation by Peabody and Broun (489). They 
confirmed the work of Osler and Gardner (480), that an 
abnormal degree of phagocytosis of red blood corpuscles 
occurs in the bone-marrow of pernicious anemia. They 
interpret the non-retention of hemosiderin granules by the 


THE BLOOD SYSTEM 35 


clasmatocytes as an indication of a very active, destruc- 
tive process in this disease. 

Mononuclear giant cells are relatively few as compared 
with normal and usually smaller in size. Such abnormal- 
ity of the megakaryocytes may, on Wright’s theory of 
the origin of blood platelets, explain the thrombocytopenia 
which accompanies the well-established anemia. 

It might naturally be supposed that, during remissions, 
when a more nearly normal number of erythrocytes is 
being delivered to the blood, that the marrow, thus giving 
evidence of physiological improvement, would likewise 
show an improved histological and anatomical picture. 
Comparatively few contributions on this point have 
appeared. Zadek’s (669, 679) case which died of inter- 
current disease during a remission was examined, but 
possibly not extensively enough to rule out the error aris- 
ing from the phenomenon described by Archibald and by 
Sheard. The right femur, left tarsus, and sternum were 
investigated. The right femur showed fat cells and nor- 
mocytes preponderating, very few normoblasts and no 
megaloblasts. Among the white blood cells, the granular 
series slightly outnumbered the lymphoid series, with ten 
per cent of the total white count made up of myelocytes, 
and no myeloblasts. In the sternum, isolated megaloblasts 
and a plentiful supply of myeloblasts were encountered. 
These findings can scarcely be regarded as conclusive evi- 
dence of a return to a normal picture. Peabody and Broun 
(489) found in a single case of a patient dying in a remis- 
sion that phagocytosis of red blood corpuscles was not a 
striking feature. From present information the conclusion 
is drawn that the bone-marrow during remissions appar- 
ently shows less of the early embryonic features and less 
phagocytic activity than during the active periods of the 
disease. 

The spleen’s softness, due partly to post-mortem change, 
was noted by Combe (128) in 1822. This organ in per- 


136 PERNICIOUS ANEMIA 


nicious anemia received comparatively little attention dur- 
ing the last century. Pepper (493), in one case, found it 
somewhat enlarged (half more than normal), the pulp 
dark and softened, but no leukemic lesions present. In a 
second case, the spleen was “slightly enlarged; the cor- 
puscles healthy; on handling it, distinct crepitation was 
perceived, owing to decomposition of its tissues, despite 
the general good preservation of the corpse. The splenic 
pulp was soft and purplish, without any leukemic patches 
or enlarged Malpighian corpuscles. Under the microscope 
the field was crowded with small round cells (smaller than 
the majority of the cells in the marrow) spindle-shaped 
cells and very pale red blood globules.” 

Warthin’s (636) eight cases showed a great range of 
differences in the splenic findings. The following three 
examples best illustrate this variability: Case VII, Spleen 
about four times the normal size; capsule stretched, 
smooth. On section, deep red in color, very soft. Trabe- 
culae and follicles covered by pulp. Microscopically: 
atrophy, acute and chronic congestion, hyaline vessels, 
increase of reticulum of pulp, great decrease of lympho- 
cytes in pulp; the majority of the cells in the pulp are large 
mononuclear cells of varying size and shape. Many of 
these contain pigment, very little of which gives the iron 
reaction. They also contain red blood cells in different 
stages of disintegration. Larger cells containing two to 
three nuclei are also numerous in the reticulum and si- 
nuses. A few large giant cells resembling those of the bone 
marrow also found. Many of the larger mononuclear 
phagocytes are colored brown or yellowish; in others the 
pigment is granular. Small collections of granular pig- 
ment of a brown color are found throughout the pulp. 
Only a small portion give the iron reaction. Case III, 
Spleen weighs two hundred and eight grams; about nor- 
mal in size and shape. Notches on the anterior margin 
well marked. Capsule slightly thickened and wrinkled. 


THE BLOOD SYSTEM 137 


Consistency soft. On section, the pulp is bluish-red, 
stroma slightly increased, follicles somewhat diminished 
in number but of fair size. Microscopically: atrophy and 
chronic congestion; moderate hemosiderosis. Case V, 
Spleen weighs ninety-six grams. Small, triangular in 
shape; small notch at the lower portion of the anterior 
margin. Capsule thickened and wrinkled. Small white 
pearly nodules scattered over the surface. Microscopi- 
cally: marked atrophy ; no hemosiderosis. 

Gulland and Goodall (240) condensed their splenic 
findings as follows: No marked or constant change was 
found in connection with the Malpighian bodies. The pulp 
showed considerable variations as regards the kind of cell 
preponderating. In most cases there was congestion, and 
normoblasts and megaloblasts in varying numbers were 
noticed. In a few cases lymphocytes definitely preponder- 
ated in the pulp. At least half the cases showed large 
giant cells ingesting red corpuscles, and sometimes also 
white cells; giant cells resembling those of the bone mar- 
row were seen in one case. In two cases there were numer- 
ous basophile cells in the pulp, and some of these showed 
the dropsical appearance noticed in those of the intestine. 
Pigment was present in varying amount in all the cases. 
Usually a certain proportion of this gave the iron reaction 
—1in some cases in very large amount. The pigment was 
found free in the pulp or in leukocytes or endothelial cells. 

Eppinger’s idea of hypersplenie, based on constrictions 
of the sclerosed splenic artery, as the cause of the disease, 
can be dismissed on account of the facts that arterioscler- 
osis of this organ occurs in non-anemic diseases, and, in 
any case, could not account for the remissions. 

Mayo (413) found the spleen frequently smaller than 
normal at autopsy but almost never smaller than normal 
when removed at operation. The average weight of fifty 
spleens at operation was four hundred grams, not includ- 
ing two exceptionally large ones, of two thousand two 


138 PERNICIOUS ANEMIA 


hundred and twenty and one thousand six hundred 
grams respectively. He considered it likely that the spleen 
was enlarged in the earlier stages of the disease and con- 
tracted in the terminal stage. He was certain that the size 
of the spleen had no relationship to the severity of the 
disease. 

It is generally considered that, whatever its size, this 
organ presents a combined picture of phagocytosis, hemo- 
siderosis, and accumulation of abnormal red blood cor- 
puscles. Slight evidence of embryonic blood formation is, 
at times, seen and represents one of the organism’s 
attempts at extra-medullary hematopoiesis. 

The liver is considerably enlarged in about half of the 
cases. In some such cases, passive congestion is a factor, 
as evidenced by the “nutmeg” appearance, but in most 
cases the enlargement is to be attributed to the disease 
itself, and specifically to the increased blood destruction 
occurring within it. The degree of fatty degeneration 
varies considerably in different cases, but is always suffi- 
cient to leave a fatty smear on the knife after sectioning 
it. The fatty change is to be seen at the centre of the 
lobules while deposition of pigment occurs at the periph- 
ery. In all cases of pernicious anemia the liver gives the 
characteristic Prussian blue reaction for free iron, al- 
though in some more intensely than in others. In the 
middle zone of the lobules, the liver cells present a necrotic 
appearance. Between these rows of necrotic cells the wid- 
ened capillaries present, within their endothelial cells, 
engulfed red corpuscles and often excessive aggregation 
of hemosiderin granules. It is a combined picture of 
parenchymatous degeneration and phagocytosis by the 
reticulo-endothelium. 

Changes in the lymph glands, first mentioned by Fer- 
rand (196) and by Quincke (510) received exhaustive 
attention from Warthin (636), who presented as the 
constant findings “dilatation of the blood sinuses and 


THe BLOOD SYSTEM 139 


evidence of increased hemolysis, as shown by the in- 
creased number of phagocytes, containing disintegrated 
red blood cells and blood pigment.” We must regard the 
hemolymph nodes of the body as organs capable at times 
(not only in pernicious anemia) of greatly exaggerating 
their normal but moderate function of blood destruction 
and also of harboring centres of extra-medullary blood 
formation, even of an embryonic type. 

B.—The fluid tissue. The bloodlessness of these pati- 
ents at autopsy represents the true gross pathology of the 
blood system and was the first feature of the disease to 
be remarked. The heart at autopsy may contain as little as 
one ounce of blood, which has a very thin, watery appear- 
ance, the clot being soft and the serum stained with bile 
and blood pigments. 

The histological features which constitute the blood 
picture of pernicious anemia are to be presented as partly 
numerical and partly morphological. Since the estimations 
of the numbers of the red and white blood corpuscles, of 
the blood platelets and of the percentage of hemoglobin 
are procedures for measuring the functional state of the 
blood system, they will be considered under the next 
section. 

The typical blood picture of pernicious anemia may be 
defined as one of severe anemia in which the red blood 
corpuscles tend to be much larger than normal, character- 
istically oval in outline and well filled with hemoglobin, 
and in which blood platelets and polymorphonuclear leu- 
kocytes are reduced in number, with the appearance, at 
times, of nucleated red corpuscles. This brief description 
must be supplemented by many remarks on the vari- 
ations in shape of the erythrocytes, and other points of 
importance. 

Such a typical blood picture occurs in the large major- 
ity of cases. Levine and Ladd (370) found it in seventy- 
six and nine-tenths per cent of one hundred and fifty 


140 PERNICIOUS ANEMIA 


cases. Christian (112) roughly estimates that a typical 
picture is to be found in but sixty per cent of cases. Such 
figures are based upon what may be found in the first 
examination of patients. A blood picture, more or less 
well-developed, will be found, however, at some stage of 
the disease in every case, with the single exception of a 
very few cases of fulminating cord change who die 
quickly without anemia. Whether the blood picture is 
typical or not, it will not suffice in itself to make the diag- 
nosis, but must be correlated with other system changes, 
viz., those in the digestion and nervous systems. 

In its typical, or fully-developed state the blood picture, 
while not pathognomonic, is almost so. Other pictures 
resembling it more or less closely will be discussed in the 
chapter on diagnosis. Even the smear appearances are so 
characteristic and so nearly limited to this disease, that 
one would be able from a stained smear alone to diagnose 
the disease with a high degree of correctness. While it is 
never advisable or necessary to base the diagnosis on the 
smear alone, the fact that it can be done with so high a 
degree of probable correctness, indicates a high degree of 
specificity in the strictly-evaluated morphological features. 

(a) The red blood corpuscles. These present the two 
important and essential features,—anisocytosis and mac- 
rocytosis. Variations in size and the presence, especially, 
of cells larger than normal, constitute the ground pattern 
upon which all other characteristics may be set. 

Anisocytosis of a mild character may antedate the 
actual anemia. It sometimes appears before any fall in 
the erythrocyte count has occurred, and sometimes, but 
more seldom, before the hemoglobin percentage has 
started to fall. A very mild degree may be found in 
achlorhydric individuals, and in those suffering addition- 
ally from arthritis deformans. This mild anisocytosis, 
while not greater than that of some simple anemias, is 
distinctive because of its occurrence without anemia. A 


THE BLOOD SYSTEM 141 


similar phenomenon in a simple anemia would be accom- 
panied by marked depression of the erythrocyte count and 
the hemoglobin percentage. Such an early anisocytosis, 
accompanied by achlorhydria, is, next to increased vol- 
ume index, the earliest indication of incipient pernicious 
anemia. 

Anisocytosis depends, of course, upon the fact of the 
presence, at one time, of three graded sizes,—microcytes, 
normocytes, and macrocytes. The degree of anisocytosis 
varies with the severity of the anemia. The most marked 
degrees are found 
during periods 

when the anemia is 
atom 7 most pronounced 
and when the blood 
serum contains the 
most bilirubin. 
This intensification 
of the anisocytosis 
is due more to the 


Fic. 1.—Curve of red blood corpuscle diameters eee of 
in case of pernicious anemia, compared with macrocytes than to 


normal (J. W. Shackle and A. C. Hampson id » 
252). a decrease in size 
of microcytes. At 
such times, a most remarkable degree of size variation 
may occur, somewhat greater than has been found even 
in those anemias which resemble the Addisonian most 
closely. The phenomenon is strikingly illustrated in a 
form of graph devised by Price-Jones (503) which shows 
the number of cells occurring at any diameter. 

It will be noted that normal blood presents a well- 
pointed and narrow peak, whereas pernicious anemia 
blood shows a much wider and flatter curve, the highest 
point of which lies well to the right of the normal peak. 
It shows at a glance the occurrence of both abnormal 
smallness and abnormal largeness, and, particularly, the 


Aoasson's Anata 


q 
c 
& 
8 
= 
S 
z 
2 


OUAHETERS Ww fl 





142 PERNICIOUS ANEMIA 


preponderance of macrocytes. This latter feature causes 
an increase in the average diameter of the red blood 
corpuscles in pernicious anemia. 

Price-Jones (503) found that erythrocytes from nor- 
mal blood had an average diameter of 7.21 yu. This was 
based on the measurement of ten thousand cells from 
twenty healthy persons. The erythrocytes from pernicious 
anemia blood had an average diameter of 8.24 yu. This 
was based on the measurement of ten thousand cells from 
twenty patients. 

The graph shown in Figure 2, indicates, in addition to 
these facts, that in the simple anemia following hemor- 
rhage, the curve is 
only slightly flat- iit o6ccntsenena 
tened and favors | 10 a Fe ge 
the microcyte side. 90 

The observations | 2°° 


370 
i S 
of Price-Joneshave | s¢ sooomeccas |] idooaidiaceie 
been confirmed by | * (Aon 20€ASES OF 
- ANAEMIA. 
several physicians 7 , = 824 ft 


(395236; 252.308) 
and indicate that 
the diameters of 
the red blood cells 


: Sr DIAMETERS IN AL 
in pernicious ane- 


Fic. 2.—Curves of red blood corpuscles diame- 





mi j j ters in healthy persons, anemia following 
la 1M relapse give hemorrhage, and in pernicious mer & 
1 ie mean diameter of red corpuscles rice- 

a very wide per ara 


centage frequency 
curve as compared with normal blood or blood in simple 
anemia. 

Bell, Thomas and Means (39) found that in spon- 
taneous remissions, or those induced by treatment other 
than liver diet, the diameter-percentage-frequency curves 
showed an approach to normal but indicated that the 
changes typical of pernicious anemia were still present 
to some degree. 


THE, BLOOD SYSTEM 143 


Medearis and Minot (427) found that in fourteen 
cases in whom remission followed the use of liver diet, 
the mean diameter of the red blood cells became normal 
in eleven cases and even less than normal in three cases, 
when the red blood cell count increased to between 4,200,- 
000 and 6,300,000 per cubic millimeter. 

Further information, particularly agreeable to the 
mathematical mind, may be gained by computing the 
median diameter and the diameter dispersion. The median 
diameter differs from the mean or average diameter. The 
median diameter is such that if its value be X, then half 
the cells present 
have diameters 
greater than X, and 
half have diameters 
less than X. In 
order to determine 
the median diame- 
ter, a summation 
frequency curve is 
first plotted on 























ey 
= 
& 
s 
K 
= 
Ss 
Ss 
= 
Q 




















6 
MICRONS 





Fic. 3.—Percentage frequency curves for the 


diameters of the red blood cells in two cases 
of pernicious anemia during relapse and marked 
remission, contrasted with normal (Medearis 
and Minot). 


arithmetic proba- 
bility paper where 


the figure for the 








Heavy solid line (- ) normal, averaged data. a 

A ( ) case 7 (table 1), red blood cells 1,200,000 per cubic millimeter fifty percen tile 
Al (-------- ) case 7 (table 1), red bloed cells 5,020,000 per cubic millimeter . 

B (--n--en eee ) case 2 (table 1), red blood cells 2,400,000 per cubic millimeter Sra d e gives the 


B! (-e-e-e-2-2-*) case 2 (table 1), red blood cells 4,500,000 per cubic millimeter 


desired determina- 
tion. This median 
diameter represents the centre of the range of the red 
blood cell diameters. From such a summation frequency 
curve another value can be computed, viz., the diameter 
dispersion, which is the difference in diameter readings 
at the eighty-four and sixteen percentile grades. The 
diameter dispersion is a quantitative measure of the 
amount of anisocytosis. 

Figures 4 and 5 show the summation-frequency curves 
in normal and pernicious anemia bloods. 





144 PERNICIOUS ANEMIA 


Figure 6 repre- 
sents the summa- 


Mh 
tion-frequency- BRRRRRERRER 
curves of pee) | 


ous anemia red 
blood cells, in re- 
lapse and in liver- 
diet remissions, as 
compared with 
normal. 

Medearis and 


Minot (427) found Seeee) Seana 
that in patients BP //Ane 


with remissions ie 
following the liver 
diet, the red cor- 


puscle diameter 
45 50 55 60 65 70 75 G0 65 90 95 100 105 10 15 





dispersion falls and D M 
LAMETERS IN MiICRONS 
aay be well eed peat us rateable. é of, digeaberor of eee 
t , 
the upper norma col dinsctery in 20 sera oe 
limit or may remain 


slighly above nor- 
mal. This means 
that anisocytosis 
may become even 
less than normally 
occurs, or be but 
slightly more than 





esses 
Chae aS 


WN TTT 
22 
BiiRVer eo aaa 


AS 


ASS 
es 
ro 








ZA 
normal. This stim- 7, jencueuee 
ulates these authors eal Lest fa 

lat to Ao sgoe /aeueeceee 
to speculate as THA EDuaeL 


Roane rs aie pet oll ch 


contains some fac- 





tor which matures REE EE EEE 
and produces cells 45 50 85 60 65 70 75 80 05 90 SMT OS NOMS eDeS oes 
at a greater rate DIAMETERS IN MICRONS 
than normal so that Fic. 5.—Curves of distribution of red blood 


cell diameters in 25 cases of pernicious anemia 


the size of the cells (Bell, a homap san Aiea): 





THE BLOOD SYSTEM 145 


is diminished. They present the following table which 
summarizes the data concerning the red blood cell size of 
fourteen cases before and after taking liver diet. 

It is of interest to note that in two or three twenty-year 
remissions, not induced by liver diet, Hurst (309) noted 
a persistence of macrocytosis. 

During any re- 
mission there is a 
lessening of the de- 
gree of anisocy- 
tosis, noticeable 
without microme- 
ter measurements, 
and proportional to 
the excellence of 
the remission as 
guaged by the 
blood counts and 
the clinical im- 
provement. In 
some good spon- 
taneous remissions 


of three years du- 
DIAMETER OF CELLS IM MICRONS x 
Fic. 6.—Summation-frequency-curves for the ration the smear 


diameters of the red blood cells in the same 


two lee of pernicious anemia for which per- looks com pata- 

centage frequency curves are given in Fig. 3 _ a 

(Medearis and Minot). = tively normal, al 
Solid line ( ) normal, averaged data. though in almost 
A (—— ———) case 7 (table 1). ved blood cells 1,200,000 per exbie millimeter 


Al (-------- ) case 7 (table 1), red blood cells 5,020,000 per cubic millimeter every field there 1S 
) case 2 (table 1), red blood cells 2,400,000 per cubic millimeter 


A eee 5) (table 4) ied toed onl €600 00 per able linda liable to appear an 
isolated macrocyte 
with ill-defined 
borders and, in the writer’s experience, deficient hemo- 
globin complement. 

The occurrence of macrocytes. The abnormally large 
red blood corpuscles constitute, as Laache (351) first 
indicated, the essential feature of pernicious anemia cel- 


& 
S 
= 
S 
ry 
= 
Ss 
zx 
= 
SS 
& 
S 
~ 
z 
= 
5 
ce) 
~ 
~ 
Ne 
) 
w 
Ss 
S 
s 
iat 








146 PERNICIOUS ANEMIA 


lular morphology. The feature becomes increasingly 
striking during severe periods of the disease and, while 
less so during remissions, seldom if ever entirely dis- 
appears. The remissions due to liver diet evidently prove 
exceptional to this statement. 

The macrocytes are characteristically of an oval out- 
line. In one case, by two-diameter measurements of all 
erythrocytes over 7 u, ovality was detected by the writer 
in eighty-nine per cent of the macrocytes. This point is 
not without diagnostic significance, for frequently enough 
a macrocytic anemia may be encountered characterized by 
macrocytes of a circular outline. 

These large oval cells are well filled with hemoglobin, 
as also, indeed, are all the erythrocytes in relapse, for it 
is practically impossible to find an instance of any con- 
siderable achromia, or of much anisochromia. Even in 
unstained, wet preparations the red blood corpuscles may 
be seen to be well filled with pigment. In stained prepara- 
tions, the macrocytes stain very distinctly, usually heavily, 
a fact dependent upon either their normal hemoglobin 
saturation or, as Bowell has suggested, upon their chem- 
ical reaction. 

The macrocytes of especially large size are sometimes 
called megalocytes. Both varieties are the chief indications 
to be encountered in an average case of disturbed blood 
formation. They are thought to arise by an abnormal type 
of maturation of the parent erythroblasts in the marrow. 
In health, the megaloblasts (very large forms with reticu- 
lar nuclei and basophilic cytoplasm), as well as their im- 
mediate progeny the erythroblasts (somewhat smaller 
cells of similar type), give rise to the normoblasts (forms 
much smaller, with pyknotic nuclei and cytoplasm taking 
either stain). The next form recognized is the nucleated 
erythrocyte, a cell of equal size to the fully matured red 
corpuscle, but possessing a pyknotic nucleus. The normo- 
blast and the nucleated erythrocyte by loss of their 


THE BLOOD SYSTEM 147 


nuclei (through absorption or extrusion) become the 
definitive erythrocytes, the adult functional red blood 
corpuscle. In pernicious anemia, this orderly process does 
not obtain. The macrocyte is considered to represent an 
erythroblast which, after loss of its nucleus, is prema- 
turely delivered to the circulation, and is, therefore, an 
indication of abnormal blood formation. 

The occurrence of muicrocytes and potkilocytes. While 
any red blood cells smaller than occurs in normal blood 
might be called a microcyte, the term is generally reserved 
for very small cells, first noted by Eichhorst (165) and 
then called Eichhorst’s corpuscles. The occurrence of 
small red blood cells is really more characteristic of simple 
anemias than of pernicious anemia. Microcytosis is num- 
erically less a feature of this disease than macrocytosis. 
To a limited extent, however, it is a feature. The exact 
mode of origin of microcytes is not clear, but the presence 
of many microcytes is taken as an indication of increased 
blood destruction. 

Poikilocytosis is a feature of pernicious anemia, but it 
often is less marked in this disease than in severe, chronic 
simple anemias. Many bizarre shapes are to be noted,— 
forms resembling Grecian urns and Indian arrowheads 
are common but many unsymmetrical forms impossible 
of verbal description also occur. 

Small, irregular, normally staining portions of red 
blood cells, not deserving to be called cells, are frequently 
encountered. They appear to have been broken off from 
an erythrocyte. In some exceptionally severe cases, espe- 
cially near death, when the accepted signs of blood de- 
struction are very marked, many, or, occasionally, the 
majority of the red blood cells present blunt-ended pseu- 
dopods, 3 or 4 to a cell, anda few actually show an oozing 
out of their stroma. Such fragmentation forms and such 
disorganized corpuscles are regarded as microscopic evi- 
dence of increased blood destruction. 


148 


PERNICIOUS ANEMIA 


TABLE 9 


The diameter of red blood corpuscles in pernicious anemia dur- 
ing relapse contrasted with their diameters during remission 
(Medearis and Minot). 


























Red blood | Mean Median 
5 cells diameter | diameter 
Ss}al/alalale|e 

ay mo.| mil-| mil-| mi- ean Peri mi- 

lions} lions} crons} crons| cron.} cons 
1 Dla cha] So 2kO)) tess) Castell Asal 
2) 20 | 2.4 | 4.4 | 8.43] 7.62) 8.71] 7.69 
Sha 7 | 3.7 | 5.1 | 8.16] 7.44) 8.18] 7.43 
alba | o- | 50 |---| 7.43) «| 7a 
5 7 | 2.8 | 4.5 | 8.30} 7.26) 8.00} 7.31 
6 2] 2.6 | 4.8 | 8.50} 7.62) 8.43) 7.61 
i 411.2] 5.0] 8.23) 7.24) 8.31) 7.25 
8 3] 1.8 | 5.1 | 7.98) 7.40] 7.93] 7.44 
9 D2 On| U5ic50|ee GO MOsSLluds8/A| anol 
10f | 2] 3.2 | 6.4 | 7.40) 7.23) 7.46) 7.25 
MS. NOLS) 05s || iri S425 | aetedl re O 
12 Th Wha) Sasi) Sf laces GI) Wa zal 
13 TPP Sale ah [ele] Ge Fae, 
14 NORE || Sssip Si | sO. Gy Pale] 
Av. | 5 | 2.1| 5.2| 8.17] 7.33] 8.19] 7.35 

















Smallest and great- | Dispersion 
est diameter 

s s 

2 a eo 

n an 

ay "2. | es che 

Vv o ovo vo 

[a4 [a4 4 4 
microns | microns | mi- | mi- 
crons| crons 
3.7-13.0 | 6.3-10.0) 3.80] 1.24 
4.0-10.0 | 5.5- 9.5) 2.54] 1.34 
5.6-10.0 | 5.5- 9.5] 1.87] 1.25 
6.2-10.0 | 5.6-10.0) 1.57] 1.32 
EE oles & 6.3- 8.8] ....] 0.96 
3.0-13.0 | 5.0— 8.8] 2.04) 1.00 
4.4-11.9 | 5.6-10.0} 2.07] 1.50 
3.8-12.5 | 5.0— 9.4) 3.37] 1.33 
5.0-11.3 | 5.6—- 9.4} 2.00] 1.30 
5.6-11.3 | 5.0- 8.8} 2.12) 1.25 
5.0- 9.4 | 5.6— 8.8] 1.70] 1.06 
4.0-11.25} 5.0—- 9.4) 2.65] 1.25 
1 5.0-10.6) g | 1.25 
1 5.6-10)4)) Some 
1 5.6- 8.8} g | 1.10 


407-1163) '5.5=9)5 |e ees 





* Previously the red blood cell count had been about 1,500,000 per cubic millimeter. 
+The lower figures (4b) are those for measurements made after patient had re- 
mained in marked remission for one year. 
t Previously macrocytosis had been marked. Liver had been eaten daily for seven 
weeks before first measurements were made. 
§ At time of relapse, there were so many small cells that the values for the average 
diameter and median were less than is usual in pernicious anemia with low red blood 
cell counts. However, there is a high dispersion. 
| Measurements were not made. The cells showed a distinct macrocytosis. Microcytes 
were plentiful and anisocytosis marked. 


tak SLOOD SYSTEM 149 


The occurrence of immature forms. Megaloblasts prob- 
ably occur in the circulation in every case of pernicious 
anemia at some stage of the disease. But in the routine 
smear examination of a number of patients they will not 
be encountered at all frequently or perhaps not be seen at 
all. While confirmatory, they are by no means essential to 
the diagnosis. Their presence even in moderate numbers 
indicates severe physiological strain upon the marrow. 
They occur in large numbers in the blast crises and are 
usually increased after splenectomy. Normoblasts, indic- 
ative of a less degree of physiological embarrassment, 
occur quite frequently in pernicious anemia, as they do 
also in severe simple anemias, and are present in large 
numbers in most blast crises. Other evidences of im- 
maturity,—polychromatophilia, reticulum, Howell-Jolly 
bodies and Cabot bodies,—will be considered presently. 
Ellerman (170) by photomicrographs in two cases of 
pernicious anemia, demonstrated the presence in the 
blood of hemoglobin-free, rudimentary erythrocytes, the 
so-called erythrogonia. 

(b) The white blood corpuscles. The polymorphonu- 
clear neutrophils show a tendency to a high number of 
lobules in their nuclei. There occur in pernicious anemia 
what Rolleston referred toas giant polymorphs, but which 
Cooke (131) refers to as macropolycytes. There are two 
forms, depending upon the nucleus. In the first, the 
nucleus and cytoplasm are normal but the cell is very 
large (over 14 » in diameter). In the second, which 
resembles the megakaryocyte of the bone-marrow, the 
nuclear bulk is great absolutely and relatively to the cyto- 
plasm and may be in the form of a band or contain from 
two to fourteen lobulations, while the cytoplasm contains 
large neutrophilic granules. The cause of the macropoly- 
cyte is unknown, but they are regarded as evidence of 
great urgency in the bone marrow activity. Cooke regards 
the second form, resembling megakaryocytes, as of grave 


150 PERNICIOUS ANEMIA 


significance since no case in his experience has lived 
beyond a few days after their appearance. 

Eosinophil polymorphonuclears were quite commonly 
found in Levine and Ladd’s (370) cases. They have been 
said to occur most numerously in the early stages of the 
disease. 

Arneth (16) found the lymphocytes mostly small, 
which is, according to this authority, tantamount to a 
right-handed shift of his scale. 

Myelocytes and even myeloblasts of the various types 
may appear in the blood, especially during blast crises or 
the agonal state. 

The blood platelets are usually larger and of more 
irregular outline than normal. 


THE FUNCTIONAL STATE OF THE BLOOD SYSTEM 


The normal function of the blood is to maintain proper 
nutrition and respiration of the tissues, to preserve itself 
in the face of hemorrhage by clotting, and to act as a 
common carrier for immune substances, hormones and 
vitamines. The normal function of the blood-forming and 
blood-destroying organs, which comprise the hemolyto- 
poietic system, is to maintain the formed elements of the 
blood in normal characters and numbers. 

The functional state of the blood system, as a whole, 
may therefore be judged, from a practical standpoint, 
through a study of the following points. (1) The balance 
between production and destruction of blood cells. (2) 
The state of the blood and bile pigments. (3) Physical 
and chemical changes in the blood. 

The oxygenation and nutrition of the tissues will be 
considered in connection with the metabolism. 

(1) The balance between production and destruction 
of blood cells. Normally blood production and blood de- 
struction proceed in a correlated manner, at an equal rate, 
so that the number of blood cells in the circulation is 


Pay BLOOD) SYSTEM 151 


remarkably constant. The blood count at any given time 
is necessarily a numerical expression of the balance in 
this profit-and-loss system. 

The profound oligocythemia which characterizes per- 
nicious anemia means, and means only, that a disturbance 
of the normal balance exists. This disturbance may be due 
to any one of the following factors. (a) A greatly de- 
creased production. (b) A greatly increased destruction. 
(c) A considerably decreased production combined with 
a considerably increased destruction. 

(a) The factors of blood production. In the normal 
adult human organism, the production of red blood cor- 
puscles and of granular leukocytes is restricted to the 
bone marrow. In pernicious anemia, the same restriction 
exists, except that a few scattered extra-medullary foci 
of hemopoietic tissue may be found at times in the spleen, 
liver, and hemolymph nodes. These later are of negligible 
importance. Whatever production occurs, occurs in the 
bone marrow. The gross and microscopic appearance of 
the marrow suggest that this tissue is hyperactive. The 
spread of the marrow throughout the shafts of the bones 
is the chief reason for thinking that abnormally great 
production is taking place. McMaster and Haessler (421) 
showed that the chief factor in causing red bone marrow 
to spread was the presence of an excessive supply of 
hemoglobin. Two series of rabbits were bled sufficiently 
to cause anemia of equal degree in the two series, but 
to one series was administered, after each bleeding, 
enough hemoglobin to compensate for that removed by 
hemorrhage. It was found that the series receiving the 
pigment showed marked extension of the marrow while 
the other series did not. This increased red marrow 
showed extreme vascularity and erythrogenic islands of 
great size, with normoblasts. The conclusion from these 
experiments was that the stroma material for making red 
blood cells was practically inexhaustible and that, if the 


BSS PERNICIOUS ANEMIA 


organism be supplied with sufficient hemoglobin, the mar- 
row would quickly spread, with evidence of increased 
blood production. It is quite possible, as Whipple sug- 
gested, that in pernicious anemia too much hemoglobin is 
produced, and this excess not only causes the spread of 
the red marrow, but its unused excess is converted to 
bilirubin. 

There is no way of being sure that the appearances of 
increased erythroblastic activity in the marrow signify a 
process which results in an actual delivery of increased 
numbers of erythrocytes to the circulation. In fact, it is 
quite possible that in spite of these appearances, the total 
numerical production is reduced below normal. If such be 
true, the bone marrow would be seen to present a feature 
of malignant tissue,—cellular hyperplasia at the expense 
of function. 

(b) The factors of blood destruction. Although in 
health the adult spleen is a more active agent in blood 
destruction than the marrow, it would appear from the 
work of Doan (149) that in pernicious anemia the rela- 
tionship is reversed, and that the clasmatocytes of the 
spleen are not as active in this respect as are those of the 
bone marrow. In the latter tissue there is a marked ten- 
dency toward the phagocytosis particularly of young, im- 
mature, nucleated red blood cells, which presumably have 
not been in the circulation. Doan’s observations did not 
indicate that the spleen takes any directly active part in 
an increased destruction of blood in this disease. This is 
of course a surprise, but tends to concentrate the atten- 
tion upon the marrow as the chief destructive agent. 
Both in the liver and hemolymph nodes increased destruc- 
tion takes place, but exactly to what comparative extent, 
is not known. 

It should be remembered in any case that, besides the 
phagocytosis of red blood cells in the clasmatocytes of the 
reticulo-endothelial system, no site or mechanism of blood 


THE BLOOD SYSTEM 1 


destruction is recognized in this disease. Whether this 
phagocytosis over prolonged periods can account, largely 
by its own effects, for the degree of oligocythemia en- 
countered is uncertain. 

(c) Combination of decreased production and increased 
destruction. Since we are aware that increased destruc- 
tion is taking place, the point lacking for this combined 
hypothesis is the question of whether or not decreased 
production exists, and it must remain for the present 
purely a hypothesis. 

The obvious fact remains that a serious disruption of 
the normal balance occurs. In few anemias can such low 
red blood counts be found. The marked oligocythemia is, 
in itself, one of the outstanding characters of the anemia. 
Cabot (90) has always emphasized this point. The lowest 
count on record is 146,000 (Quincke), while counts of 
500,000 per cubic millimeter are not at all uncommon. 
During the first attack, the numbers usually descend to 
2,000,000 per cubic millimeter, the descent being more 
rapid at first and slower later. On the other hand, during 
a remission, the rate of increase is more rapid at first and 
slower the higher the numbers become. At the beginning 
of an attack, very rapid falls may, in exceptional cases, 
occur, so that the counts may descend from normal to 
2,500,000 per cubic millimeter in a period of three weeks, 
instead of six months as usual. So, too, in remissions, 
exceptional rapidity of increase may occur. The writer 
has seen the red blood count rise, within a period of five 
days, from 900,000 to 3,500,000 per cubic millimeter. 
Aside from such unusual instances of rapid rise and fall, 
there is an average curve in which the stage of increase 
and decrease each extend over a period of six months. 
The condition of the patient does not parallel the red blood 
counts at all times, especially not when this count is over 
2,000,000 per cubic millimeter. This is shown by the fact 
that some patients can do manual labor with a count of 


154 PERNICIOUS ANEMIA 


2,500,000 while others may die with a count of about 
3,000,000 per cubic millimeter. Changes in the blood 
volume will, as in any anemia, influence the blood counts. 

A leukopenia also exists, and except in early stages, or 
in the presence of associated infection, is a diagnostic 
point of importance. The degree of leukopenia is roughly 
proportional to the anemia, becoming less during periods 
of improvement. Total white blood counts as low as 1500 
to 2000 per cubic millimeter are not uncommon during 
severe stages. The condition is one of leukopenia with 
lymphocytosis, but Arneth (16) found a low absolute 
number both for polymorphonuclear neutrophils and lym- 
phocytes. He, as well as Briggs and Coates have found 
that the polymorphonuclear cells show a right-handed 
shift on the Arneth scale. Thus Arneth found that neu- 
trophils with two nuclear segments decreased from the 
normal thirty-five per cent to sixteen per cent. He con- 
siders the smallness of the lymphocytes equivalent to a 
right-handed shift (or “negative reaction’). 

The blood platelets are reduced in the well established 
anemia, but not necessarily in the earlier stages. The 
blood platelet counts vary, usually from 50,000 per cubic 
millimeter down to a virtual absence. Allard (7) has sug- 
gested a platelet index, which is a figure obtained by di- 
viding by fifty the number of platelets per one thousand 
red blood cells. These figures are chosen because, taking 
two hundred and fifty thousand per cubic millimeter as a 
normal count, this would give a proportion of fifty blood 
platelets to one thousand red blood cells, or a normal 
index of 1.0. In pernicious anemia he finds the platelet 
index low, usually 0.2 or less. As will be seen subsequently 
the blood platelet count is a useful guage of the bone 
marrow vitality. 

The bone marrow condition as reflected in the circulat- 
ing formed elements. It is but‘natural to suppose that the 
visible products of the bone marrow would convey impor- 


ti BLOOD SYSTEM 155 


tant information with regard to the functional state of 
this tissue. At least three somewhat distinct functional 
conditions of the bone marrow may be recognized :— 
regeneration, depression and exhaustion. 

The marrow in an early state of regeneration is some- 
times said to be in a state of stimulation. The signs of 
regenerative activity are of both a negative and positive 
character. The negative signs are the reduction or disap- 
pearance of the degree of bilirubinemia, the gradual dis- 
appearance of the more striking evidences of abnormal 
formation, and a lessening in the number of fragmenta- 
tion forms and of poikilocytosis. Among the positive signs 
are polychromatophilia, stippling, the presence of mod- 
erate numbers of blasts accompanied by increased num- 
bers of reticulated cells, Cabot ring-bodies, Howell-Jolly 
bodies, increased numbers of blood-platelets, increased 
numbers of leucocytes, rising counts for the red blood 
cells, and increasing values for the hemoglobin percen- 
tage. 

While the bone marrow in this disease has always been 
thought of as being in a constant state of stimulation, 
sudden regenerative signs frequently follow certain 
forms of treatment. The regeneration sometimes follow- 
ing blood transformation and administration of arsenic 
does not differ materially from the spontaneous regener- 
ation at the beginning of a remission. Splenectomy how- 
ever does furnish an example of a means of bone marrow 
stimulation, since it is nearly always followed by a lessen- 
ing of bilirubinemia, and the appearance in the circula- 
tion of youthful forms, particularly blasts and red blood 
cells exhibiting Howell-Jolly bodies, Cabot bodies, retic- 
ulum, increased blood platelets and leukocytes. Whether 
or not the splenectomy is followed by a satisfactory rise 
in the red blood count, the delivery by the marrow of 
these elements, and their persistence in the circulation 
often for months, indicate the lifting of a mysterious re- 


156 PERNICIOUS ANEMIA 


straint which the spleen exercises upon the delivery of 
immature blood cells by the marrow. The liver diet, judg- 
ing by the description by Minot and Murphy (447) of 
its effect on blood regeneration, is to be regarded as an- 
other example of a procedure which causes marrow stimu- 
lation. Following liver diet, within two weeks the bili- 
rubin in the blood drops to normal or subnormal levels, 
there occurs a rise of reticulated cells from 1.0 per cent 
to 8.0 and even 15.5 per cent within the first ten days, 
subsiding by the fourteenth day, while the red blood cell 
count rises gradually in a graceful curve to normal or 
hypernormal figures. 

Reticulated cells are young red blood corpuscles, usu- 
ally but not always larger than normal size, which, when 
appropriately stained, show within the cytoplasm the 
well-defined remains of nuclear material. Sometimes this 
reticulum has the appearance of iron filings attracted to 
the centre of the cell. Sometimes it is uniformly distri- 
buted throughout the whole cell in little patches. More 
is present in some cells than others. The type of reticulat- 
ed cell which indicates the best regenerative activity on 
the part of the bone marrow is one in which the reticulum 
is here and there gathered into firm knots. If, when using 
brilliant cresyl blue as the vital stain, followed by 
Wright’s stain, there are seen, in addition to numerous 
reticulated cells, certain erythrocytes whose cytoplasm 
takes a peculiar grayish tint, this phenomenon may also 
be viewed as favorable. Ordinarily in pernicious anemia 
blood from 1.0 to 2.0 per cent of reticulated cells occur 
and any considerable increase in their number may be a 
sign of an imminent blood remission. An increase in re- 
ticulated cells is usually accompanied by the presence of 
blasts. If the blasts are moderate in number, the infer- 
ence is that an orderly regeneration is occurring, but if 
the blasts are present in very large numbers, the signifi- 
cance is the opposite. 


THE BLOOD SYSTEM 15/ 


Cabot ring-bodies appear in the form of rings, rosettes, 
- figures-of-eight, double-threaded rings, intertwined rings, 
and rings composed of dots. They may occur in 
stippled or non-stippled cells. They may even be extra- 
corpuscular. They are nuclear remains and probably rep- 
resent the peripheral portion of the nucleus. They usually 
occur in cells taking the basic stain. Absent from normal 
blood or normal bone marrow, they may be found in lead 
poisoning, leukemia and other severe anemias. They indi- 
cate an abnormal process of maturation and furnish evi- 
dence of blood regeneration under difficulty. Munro and 
McCluskie have recently shown that by overstaining with 
Giemsa’s stains for 30 minutes or longer, Cabot bodies can 
be either stained or rendered visible as negatives in a 
much larger number of cases than formerly supposed. 

Cells which contain ring-bodies may also contain baso- 
phile granules or Howell-Jolly bodies, or both. A Howell- 
Jolly body (Howell body, Jolly body) is a nuclear rest, 
intermediate in size between a nucleolus and a granule. 
It is well defined and usually single, gives all the color 
reactions of chromatin and is a result of pyknosis of the 
nucleus. The large granule, which is sometimes seen at 
one point in the circumference of a ring-body is probably 
of this nature. Like the ring-bodies, these Howell-Jolly 
bodies imply in the first place immaturity of the erythro- 
cyte and, in the second place, a pathological mode of ma- 
turing. (For further information on ringbodies and 
Howell-Jolly bodies references should be made to Cabot 
(89), Gruner (239), Barker (23), Schleip (557), Fer- 
rata and Viglioli (197), and Naegali (467) ). 

The bone marrow, in a state of depression, is com- 
paratively inactive. The evidences of depression of func- 
tion are the absence of the signs of regeneration, marked 
degree of disturbance of cellular morphology, falling or 
stationary red and white cell counts and scarcity of 
blood platelets. 


158 PERNICIOUS ANEMIA 


The bone marrow in a state of exhaustion is much as 
described in the preceding paragraph, but additional and 
important evidences are the occurrence of purpura and 
blast crises. The appearance of many petechial hemor- 
rhages in the mucosae and skin indicates a functional 
purpura due to very great reduction in the number of 
platelets. This thrombocytopenia may occur with purpura 
in a number of different conditions, but its significance 
in pernicious anemia is very unfavorable as an indica- 
tion of marrow exhaustion. 

The most dramatic spectacle in this anemia, if not in 
the whole field of hematology, is the agonal blast crisis, 
during which the bone marrow furnishes the blood 
stream with samples of almost every kind of blood cell 
that may ever be seen there,—megaloblasts, normoblasts, 
reticulated cells, polychromatophilic cells, myeloblasts and 
myelocytes. As Minot (440) remarks, only the definitely 
achromic erythrocyte is lacking from this vivid catalogue. 
An agonal blast crisis is a wholesale delivery of marrow 
products in response to a desperate bodily demand. Inas- 
much as this “showing of its hand” by the marrow be- 
trays its real poverty in mature and functional cells it is 
of very unfavorable prognostic significance with regard 
to life. Nevertheless such blast crises may at time be 
followed by good remissions. 

(2) The state of the blood and bile pigments. The for- 
mation of bile pigment from hemoglobin was once con- 
sidered a proprietary function of the liver parenchyma. 
But owing to the work of Whipple and Hooper (647), 
McNee (422), Van den Bergh and Snapper (621), and 
Mann et al. (397, 398, 399), it is now recognized that, 
in addition to the liver parenchyma, the reticuloendothe- 
lium both in the liver and elsewhere, as well as vascular 
endothelium and serous mesothelium generally, not only 
can, but constantly do, metabolize hemoglobin into bili- 
rubin. Whipple’s (645) conception of the relations of bile 


THE BLOOD SYSTEM 159 


pigment to other body pigments has been illustrated by 
him in the following figure: 

Hemoglobin liberated in the blood stream is apparently 
not all eliminated as bilirubin by the liver, but some of it 
seems to be utilized, after undergoing reduction to the 
unknown unit structural factors, for the building up of 
new hemoglobin (315, 316). It has been shown that in- 
jections of hemoglobin in anemia increase the rate of new 
hemoglobin construction, presumably by absorption of 
substances concerned with the “pigment complex” (273), 
but feeding of hemoglobin, bile pigment, fresh or cooked 
blood, or the diges- 
tion products ob- 
tained from blood, 
does not increase 


oo 7a the bile pigments of 
(~~) — | bile-fistula animals 
ARS (274). Contrary to 


the hypothesis of 
(—)— Wilbur and Addis 
(654), of a con- 
Fic. 7.—Graphic illustration (Whipple) of the servation of bile 
relations of bile pigment to other body pig- A 
ments. pigment factors by 
absorption from 
the intestine and reconstruction into hemoglobin, the 
work of Whipple and Hooper (273, 274) affords no evi- 
dence of such absorption. In bile-fistula dogs under ob- 
servation for two years these investigators found no 
evidence of pigment lack, no anemia, no fall in pigment 
production and no reaction to the feeding of bile pigments 
(645). 

The amount of bile-pigment excreted by the liver de- 
pends partly on liver function and partly upon the amount 
of hemoglobin waste products in the body. The liver 
possesses a constructive function and not a simple passive 
eliminative function (649). In bile fistula dogs, maximal 


S 





160 PERNICIOUS ANEMIA 


bile pigment elimination occurs under certain conditions, 
for example, a combination of splenectomy and anemia 
(276): 

The suggestion of Whipple (645) that the liver paren- 
chyma and the Kupffer cells may be able to reverse their 
function of forming bilirubin from hemoglobin, affords 
a possible explanation for a partial source of hemoglobin. 
Such a hemoglobin-producing function might with equal 
reasonableness be ascribed to the marrow reticulo-en- 
dothelium, in spite of the fact that these cells are be- 
coming so heavily laden with duty—particularly with 
the important function of producing the red blood cells 
themselves (150). 

Urobilin is probably formed in the liver under abnor- 
mal conditions of the biliary tract and in the intestine by 
the action of digestive juices, possibly by bacteria. 

The bile pigment substances in the bile (bilirubin, 
biliverdin, urobilin) are not absorbed by the intestine and 
are lost to the body as true excretory products. 

With this brief survey of the present position of the 
normal pigment metabolism, it is in order to consider the 
pigmentary condition in pernicious anemia. 

The hemoglobin is found thoroughly filling the red 
blood cells. Since these cells have an increased average 
volume, the total amount of hemoglobin is greater in pro- 
portion to the number of cells than in simple anemias. 
Such is expressed in the commonly high color index. 
Much criticism may be offered as to the degree of accu- 
racy obtained by the ordinary clinical hemoglobinometers. 
The differences obtained by more accurate methods are 
not sufficiently great to negative the general impression, 
which has grown up with the subject, that a high color 
index usually obtains in pernicious anemia. A diagnosis 
of pernicious anemia is not infrequently possible how- 
ever in the presence of a color index less than 1.0. Indices 
below 1.0 are sometimes encountered, particularly during 


THE BLOOD SYSTEM 161 


the early stages of a relapse or a remission. Panton et al. 
(482) found among 117 cases, three individuals in whom 
the color index was persistently below 0.7 throughout the 
period of observation. Autopsy on these 3 cases confirmed 
the diagnosis. These authors regard 0.7 as a high index 
in the presence of severe anemia. Campbell and Cony- 
beare (98) found 0.96 as the lowest in a brief series of 
selected cases. They felt the color index could be as low 
as 0.7 in pernicious anemia, and made the point that 
many healthy persons show a color index of 0.9 or even 
0.8. Faber and Gram (189) report a case of true perni- 
cious anemia in which the color index during a remission 
and part of a relapse resembled that of a simple anemia. 
They furnish the following instructive table: 


Taste 10 


Variations in color index at various stages of disease (Faber 
and Gram). 


we 
Vv 
3 rs 
u ” $ 
: E py) Se BS Se 
& g a ga ee ge 
% 8 3 o 5 fw 2 = 
Color Index S = < at goad 
At time of admissions 
(OSME@XAMMINALIONS) 0 fccesccesccccescscee: | 1.05 1.45 91 9 0 
At acme of remission 
(G4eexaminations)) geese 19 08 1.3 ks AWE) 
Before discharge in unimproved 
or deteriorated condition 
(iexaminations) yp ee 1.9 1.35 1.6 OO 
aisty before jdeathy) ..2..c.c5210 2s cceaece ee 2.15 0.9 1.5 88 12 


It will presently be seen from the use of the “saturation 
index” by Haden, that although the average red blood 
cell in pernicious anemia is larger than normal, and there- 
fore contains more hemoglobin, it is not more highly sat- 
urated with this pigment than is the average normal red 
blood cell. 

The color index, when computed from strictly accurate 
data, is a very convenient method of forming an estimate 


162 PERNICIOUS ANEMIA 


of the increase in volume of the average red blood cell. 
A plus index is highly characteristic of pernicious anemia. 

The fact that all the erythrocytes in the circulation in 
this disease are normally saturated with this iron-con- 
taining pigment, combined with the fact that an abnor- 
mally high amount of bilirubin occurs in the plasma, 
renders it difficult to believe that any dearth of iron exists 
in the body, and still more difficult to accept the hypothesis 
that iron deficiency plays any etiological role. 

The hemoglobin in pernicious anemia contains a nor- 
mal proportion of iron, shows a normal combining power 
for oxygen (368), and retains its crystalline character 
(11). Characteristic absorption bands for oxyhemoglobin 
may at times be seen in the serum (73). Free hemoglobin 
may appear in the serum (73) and give it a bright pink 
color in markedly severe cases and especially just before 
death. Hematin has been found in the serum (73). In an 
organism so evidently surcharged with pigment it might 
be expected that any further sudden increase of hemo- 
globin could not be accommodated. Sellards and Minot 
(570) have actually demonstrated that the bodily toler- 
ance to hemoglobin is reduced. By intravenous injection 
of graded doses of specially prepared hemoglobin solution 
into patients with various types of anemias or diseases 
without anemia, as well as into normal controls, they 
found that a lowered kidney threshold occurred in per- 
nicious anemia and acholuric jaundice, because patients 
with these two diseases excreted hemoglobin in the urine 
after doses which, when given to controls or cases of 
simple anemia, caused no hemoglobinuria. 

Hemoglobinuria may accompany exceptionally severe 
stages of the disease, in some cases (334, 508). Hourly 
variations in the percentage of hemoglobin occur, but are 
less than normal variations (436, 511). Lehman has 
shown a parallelism between the decrease of fever and 
increase of hemoglobin in this disease (365). 


THE, BLOOD SYSTEM 163 


Hemosiderin, a yellowish-brown, iron-containing pig- 
ment, formed from the disintegration products of free 
hemoglobin, is deposited in the outer portions of the liver 
lobules, in the spleen and in the kidney, where it may be 
detected, post mortem, by the familiar Prussian blue 
reaction. Hunter (290), the first actually to determine the 
degree of siderosis in these tissues, found that the liver 
reached a higher iron saturation than other organs in 
pernicious anemia, and a higher and more constant satur- 
ation than the livers in other forms of anemia. Combining 
his own gravimetric results with those of others he fur- 
nished the following figures for comparison: 


TABLE 11 


Average percentage (by weight) concentration of iron in vari- 
ous organs (Hunter 300). 





No. of 

Condition Cases Liver Spleen Kidney 
fealttiy treet teeth: Co 2 BELL ele 4 0.080 0.231 
Permictous» Anemia) 22.2.2 ).22.-- 12 0.325 0.175 0.064 
Wasting Diseases). 4 0.053 0.115 0.003 
Hemorrhagic Anemia ...... 3 0.019 0.023 
Ankylostomiasis ......... nO 0.077 0.478 
D. Latus Anemia ..... ee: 0.214 0.366 
Beukemiayee).-: 4 0.238 0.159 0.086 
Chronic Malaria (25 1 0.257 0.110 


It will be noted that while the liver siderosis is greatest 
in pernicious anemia, the livers of bothriocephalus anemia, 
leukemia and malaria show comparable figures. Further- 
more, the degree of siderosis of the spleen and kidney do 
not parallel that of the liver in pernicious anemia. 

Hunter rightly regarded this extreme hepatic siderosis 
as very highly characteristic of pernicious anemia. He 
regarded it, additionally, as an evidence that the blood 
destruction, which he believed to be the fundamental pro- 
cess in the disease, was taking place in the portal area of 
the circulation, induced by the absorption of intestinal 
poisons. This viewpoint does not receive very wide cur- 
rent acceptance, partly through lack of proof of such 
portal blood destruction, and partly because of the experi- 


164 PERNICIOUS ANEMIA 


mental work of McMaster, Rous and Larimore (420). 
They showed that the repeated introduction of small 
amounts of free hemoglobin into the general circulation, 
by the subcutaneous route, led to an identical siderosis. 
Larger amounts of hemoglobin caused a renal pigmenta- 
tion equal to, or exceeding, the hepatic, a fact in keeping 
with what is know of the physiology of hemoglobin ex- 
cretion, and of the findings in human being after out- 
spoken hemolysis. In view of this work, as well as that of 
Haessler, we can only regard the deposits of iron-con- 
taining pigment in the liver, spleen and kidney as an 
evidence that free hemoglobin, in excess of that which is 
utilized by body cells, occurs in the circulation. The bone 
marrow, according to Peabody and Broun (489), is sur- 
prisingly free from pigmentation. Rous (540) has shown 
that siderosis of the kidney, in certain other diseases as 
well as pernicious anemia, may be detected by finding in 
the urine granules of hemosiderin, both extracellular and 
intracellular. 

Bilirubin exhibits in pernicious anemia three departures 
from its normal physiological behavior. (a) It is increased 
in the blood plasma, serous fluids and tissues generally. 
(b) This plasma bilirubin is slightly altered in its physio- 
chemical state. (c) It is increased in the bile. 

In health bilirubin appears in the blood plasma but in 
very high dilution (one or two parts per million). In per- 
nicious anemia and several other conditions, it is greatly 
increased—a condition referred to as hyperbilirubinemia. 

The increase of bilirubin in the bile is a condition re- 
ferred to as pleochromie. 

In pernicious anemia, acholuric icterus (hemolytic 
jaundice), and other conditions where hemoglobin occurs 
free in the plasma, the bilirubin of the plasma is in a some- 
what different form from that in which it is present in 
biliary obstruction. The differences are indicated by sev- 
eral facts. In obstructive jaundice the bilirubin appears 


THE BLOOD SYSTEM 165 


in the urine, invariably stains the body tissues, and dia- 
lyzes more or less readily through a parchment sac. In 
pernicious anemia, the bilirubin is never excreted by the 
kidney, may or may not stain the body tissues, and will 
not, as a rule, dialyze from the plasma (48). 

This altered bilirubin behaves differently in the diazo- 
reaction, oxidizing less readily, a fact utilized by van den 
Bergh (618, 619, 620) to establish a valuable differential 
test. Whereas a “prompt direct” van den Bergh reaction 
is given by bilirubin in obstructive jaundice, a “delayed 
direct” reaction is given by the bilirubin in pernicious 
anemia, hemolytic jaundice and other conditions in which 
free hemoglobin occurs in the blood. This difference in 
the bilirubin is presumed to be due to the fact that in 
obstructive jaundice the pigment in order to reach the 
blood must traverse the liver cell and is altered in some 
way during its passage. 

The jaundice of pernicious anemia is usually of a lemon 
or grapefruit hue and not so frankly yellow as in biliary 
obstruction. The sclera, the subcutaneous fat, and the 
serous fluids of the body are all stained by bilirubin. But 
definite hyperbilirubinemia may be present in this disease 
without any jaundice, in a considerable proportion of 
cases. On the other hand, jaundice always means that 
hyperbilirubinemia is, or has very recently, been present. 

The reports by van den Bergh (619, 620), Gram (217), 
and Lepehne (366) were confirmed by the valuable re- 
port of Broun, Ames, Warren, and Peabody (73) ; all of 
these indicated that high values for plasma bilirubin 
occur constantly in pernicious anemia, during active peri- 
ods of the disease. In the following table from the report 
of Broun et al., cases 1, 2, 3, and 6 show only moderate 
increases, but these, at the time of the observation, were 
clinically in a stage of remission. 


166 PERNICIOUS ANEMIA 


Tas_e 12 
Plasma bilirubin in pernicious anemia (Broun et al.). 
Red 
Corpuscles Hemoglobin Plasma 
Case No. millions (Haldane Scale) “Direct” diazo bilirubin 
per cu. mm, per cent reaction mg. per 100cc. 

Ty cane ee a 4.128 105 Delayed 13 

Db is Db ane bale, ite 2.392 76 Delayed 0.8 

HERERO E CRO gn EN 2.136 59 Delayed 1.0 

AN Aa) ee een ee 1.992 50 Delayed 22, 

eee) eye 40 dan, 1.840 50 Delayed 1.2 

tee ee a ee ad 1.704 61 Delayed 1.1 

AeA ea A eG 1.600 38 Delayed 18 

OS eek eee sae cata 1.500 42 Delayed 2.0 

Pe at he AE 1.420 30 Delayed 1,7 
LOY 2a OE Sica 1.208 35 Delayed Zz 
Un Eee Ae Beh ete wea ls 1.200 24 Delayed 1S 
11745 Selle HERSSURE Di ita 1.192 35 Delayed 2.0 
Ue WRN Bh eg RE 1.072 30 Delayed 2.3 
TAAL IRL eS aca 1.028 35 Delayed 2.0 
15) ee ee eae 0.936 30 Delayed 3.3 
1G) jee een ae 0.928 35 Delayed 1.0 
1/2 Serene 0.888 26 Delayed 1.0 
18 pee eee 0.850 20 Delayed 1.3 
Le ee ee Ps ae | 0.848 22 Delayed 3.4 
20) Re See 0.824 22 Delayed 1.0 
7A ie Har Toke tee bd 0.656 19 Delayed 1.9 
22) Bees eee ae 0.540 14 Delayed 1.0 
BSrAs died Me TeV ERE. 0.592 23 Delayed 1.9 
Vhs Keak Oh Hy AS otiaree Ly 0.584 17 Delayed 28 
ZO eals Sen Ns oem 0.569 16 Delayed 2.5 
4 Sicha doe te Be oe, dese 0.480 17 Delayed 4.0 
Zaye ot Os Sree 0.472 12 Delayed 28 
(23) \ ee eae eet 0.456 10 Delayed 2.5 


The next table shows the findings in cases of simple 
anemia due to various recognizable causes. It will be noted 
that whereas in pernicious anemia a delayed reaction was 
obtained, in these secondary anemias the direct reaction 
was negative. 


Case No. 


38 
39 


41 


Red 
Corpuscles 


millions 


per cu.mm. per cent 


1.500 
2.128 
4.360 
2.640 
5.272 
2.360 
1.264 
3.672 


2.672 


1.820 
2,792 


2.880 


3.170 


THe BLOOD SYSTEM 167 
TABLE 13 


Plasma bilirubin in secondary anemia (Broun e¢ al.). 


Hemoglobin 
(Haldane Scale) 


32 
25 


21 
51 


25 


“Direct’’ diazo 


reaction 


Plasma 
bilirubin 


Diagnosis 


mg. per 100 cc. 


Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 


Negative 


Negative 
Negative 


“Prompt” 


“Prompt” 


0.1 
0.1 


2.0 


9.6 


Chronic nephritis 
Chronic nephritis 
Pulmonary tuberculosis 
Pulmonary tuberculosis 
Bleeding hemorrhoids 
Bleeding hemorrhoids 
Bleeding duodenal ulcer 
Banti’s disease. Gastric 
hemorrhage 
Primary carcinoma of 
kidney with liver meta- 
stases, not obstructing 
the larger bile ducts 
Carcinoma of sigmoid 
Rhabdomyosarcoma _ in- 
volving pleura, pericar- 
dium and other thoracic 
structures 
Carcinoma of stomach 
with liver metastases 
Carcinoma of head of 
pancreas involving the 
common bile duct 


The next table indicates that a delayed direct reaction 


may be obtained in certain conditions other than per- 
nicious anemia; in some of the cases the degree of 
bilirubinemia is indistinguishable from that of pernicious 
anemia. 


168 PERNICIOUS ANEMIA 


TABLE 14 


Anemia with plasma bilirubin; findings similar to pernicious 
anemia (Broun e¢ al.). 


Co) 
a me 3 é 
9 3 < | = b=) 3 & @ 
a gos 8.2 ES E 
So Como Eva R= 75) Ou en 
3 o% o ag 8 oh) 
Oo (5) ie} ww ee Ay QA 
millions mg. per 
per cu.mm. per cent 100 cc. 
42 2.000 Delayed 2.7 Familial hemolytic 
jaundice 
43 1.992 58 Delayed WY Sprue 
de 2.552 58 Delayed 1:3 Anemia following alco- 


holic intoxication 
45 3.808 50 Delayed 2.0 Lymphatic leukemia 


46 2.208 40 Delayed 0.5 Post partum anemia 

47 1.174 24 Delayed 0.8 Subacute bacterial 
endocarditis 

48 2.690 49 Delayed 0.9 Subacute bacterial 
endocarditis 

49 4.840 82 Delayed 1.0 Typhoid fever 

50 4.840 112 Delayed ed Lobar pneumonia 


These observers noted also that the plasma bilirubin 
curve in pernicious anemia usually rises during periods of 
exacerbation of the clinical symptoms and falls to more 
normal levels during periods of remission. 

They noted a customary reduction in plasma bilirubin 
following blood transfusion, a phenomenon of uncertain 
significance, but owing probably to a slowing of the blood 
destruction, an increased utilization of the pigment, or 
a temporary increase in the ability of the liver to excrete 
pigment. 

The colorimetric determination of the degree of plasma 
staining, by comparing with a standard solution, but 
without reference to the behavior of the diazo-reaction, 
gives the icterus index, which is a useful quantitative 
expression of the degree of jaundice. 


fae BLOOD SYSTEM 169 


The method of Meulengracht (431), or preferably the 
modification suggested by St. George and Brown (596), 
is easily employed. The latter observers, employing their 
modification, found that the icterus index, rationally in- 
terpreted, is a distinct clinical aid in the differentiation of 
the anemias, for while simple anemias have generally low 
indices below the normal range, pernicious anemia and 
frankly hemolytic anemias have indices above the normal 
range. They found the method valuable in differentiating 
from pernicious anemia the severe pernicious-like anemia 
found sometimes in cases of gastric carcinoma, for in the 
latter the index is below the normal range. It is to be 
remembered, as they specially emphasize, that co-existing 
factors, such as pneumonia, cardiac insufficiency, and 
chronic sepsis (especially in the biliary system) may in- 
crease the icterus index above its customary range in any 
given type of case; and that hemorrhage, especially con- 
stant oozing, may lower the index below its customary 
range. In cases of pernicious anemia they employed the 
index to foretell the occurrence of remissions and re- 
lapses. 

Broun et al. (73) found in the plasma in very severe 
cases with low red blood counts, an ether-soluble pigment 
which was of very grave prognostic significance, and 
occurred in large amounts post mortem. It was of the 
nature of a lipochrome, failed to give the diazo-reaction 
and gave negative tests for lutein. 

The pleochromie, or excessive biliary excretions of bili- 
rubin, which is an undoubted feature in relapses, is not 
perfectly understood. Schneider (559, 560, 561, 562) be- 
lieves it to be constantly present even during remissions 
and to constitute an expression of the immediate hemoly- 
sis. Sonnenfeld (583), estimating the amounts of bili- 
rubin in the duodenal fluid during remissions and re- 
lapses, found as a rule twenty times smaller amounts dur- 
ing periods of improvement, although two cases in mod- 


170 PERNICIOUS ANEMIA 


erate remissions showed only three to four times less 
than those in frank relapse. Sonnenfeld was at a loss to 
explain these two cases and mentioned the possibility, as 
pointed out by Strausz and Hahn, that a mixture of cystic 
bile may simulate a pleochromie of the duodenal fluid. 

Urobilin is normally excreted in small amounts in the 
urine and is found in small amounts in the duodenal fluid 
and the stools. Urobilinogen is not normally found in the 
urine, duodenal fluid or stools. In pernicious anemia, 
urobilin is found in greatly increased amounts in the 
urine, duodenal fluid and stools, and urobilinogen ap- 
pears in these three products. There can be little question 
that a true wrobilinocholie exists in many cases as Schnei- 
der and as Giffen et al. (224) believe. But Hansman and 
Howard (254) noted an absence of urobilinogen in the 
duodenal fluid in two of five cases of the disease, although 
these two cases showed increase of this pigment in the 
stools. Scholz’s (563) findings in the urine and stools 
were not constant, and he concluded that while the urobil- 
inogen content of the stools has only slight differential 
value, a marked urobilin content can determine the degree 
of blood destruction. Robertson (531) in a study of 
eleven cases of the disease found urobilin increased in the 
stools, its amount serving as an index to the severity of 
the anemia. McCrudden (415) confirmed this finding. 
Hansman and Howard (254) estimated the urobilin and 
urobilinogen in the urine and stools of 27 cases of the 
disease. Their patients were divided into four groups on 
the bases of the red blood cell levels. Their results may be 
tabulated as follows: 

TaBLeE 15 


Pigment excretion in relation to blood levels (Hansman and 
Howard 254). 


Total average of urobilin and 
Red blood cells urobilinogen in urine and 


per cubic centimeter stools 
Gronp ile ee a ee 4,000,000 to 5,000,000 40,400 
Groupecieee ee eee 3,000,000 to 4,000,000 12,400 
Groupie eee see ee 2,000,000 to 3,000,000 98,565 


Group 4) eat ee 1,000,0000 to 2,000,000 62,950 


THE BLOOD SYSTEM 171 


The phenomenon of low output of pigment in group 
2, in the presence of relatively high blood count, they ex- 
plain by considering these patients to be, on the whole, 
in process of remission. The greatest excretion of pig- 
ment occurred at the blood level represented by group 3. 
They concluded that an increase of the urobilin and uro- 
bilinogen above 12,000 dilutions is a constant finding in 
this disease during the periods of remission; that the 
presence of even small amounts of urobilinogen in the 
urine is evidence of a probable pernicious anemia in the 
absence of signs of biliary or hepatic disease; that a low 
red blood cell count.with a low urobilin and urobilinogen 
figure indicates an arrest of the activity of the disease 
process and anticipates a remission; and that a high red 
blood count with a high pigment output often precedes 
a relapse. 

Schneider regards the increased urobilin and urobili- 
nogen excretion as an expression, not of the “immediate 
hemolysis”, but of the “heaped-up pigment in the portal 
system.” He further believes that splenectomy immedi- 
ately and permanently reduces excretion of excessive 
pigment to a normal level, thus doing away with pleo- 
chromie and urobilinocholie. He finds that where the 
blood picture and clinical picture of pernicious anemia 
recur after splenectomy these two features of excessive 
pigment execretion are lacking, although a distinct rise 
in pigment output could be observed in one of his cases 
after thirteen months. While this point still requires in- 
vestigation, few perhaps will follow him in his belief that 
fully-developed pernicious anemia is the late bone-mar- 
row exhaustion from a primary hemolytic process, with 
the spleen in the role of the chief instrument of blood 
destruction. 

Hooper and Whipple (275) obtained from the gall 
bladder bile in an autopsy of a case of pernicious anemia 
an unusual pigment which had to be treated with active 


72 PERNICIOUS ANEMIA 


acetaldehyde before it would give the usual bile pigment 
tests. 

The true significance of these various abnormalities of 
the pigment behavior cannot be said to be definitely estab- 
lished. They have customarily been regarded as evidences 
of increased blood destruction. The following pertinent 
paragraphs of Whipple (646) indicate that a different 
view may be advisable: 

“We are told that the stercobilin in a case of pernicious 
anemia is an index of blood destruction. Let us examine 
some of these figures and, further, let us assume the 
normal red cell count as 5,000,000 and the pernicious ane- 
mia count as one million for the sake of simplicity of 
comparison. If the anemia red cells disintegrate at the 
same rate of speed as the normal control, and if these 
products result in bilirubin and then stercobilin we must 
say the stercobilin figures should be one-fifth of normal. 
But the stercobilin figures during periods of remission in 
pernicious anemia often exceed twice or three times nor- 
mal stercobilin excretion, making no allowance for simi- 
lar pigments in the urine. This can only mean that the 
pernicious anemia patient with one-fifth the number of 
red cells and two or three times the amount of stercobilin 
output must regenerate its total red cell mass every three 
days instead of the assumed normal every thirty days. 
The normal replacement factor for red cells and hemo- 
globin is believed to be three per cent per day. We must 
postulate from thirty to forty per cent replacement of red 
cells per day in a pernicious anemia case if we persist in 
explaining the stercobilin content as being due to blood 
destruction. Those who wish to accept this explanation 
are welcome to do so, but it would be a fleeting and trou- 
blous life period endured by the red cell in pernicious 
anemia. 

“Our conception of pernicious anemia is that there is a 
scarcity of stroma building material or a disease of the 


THE BLOOD SYSTEM 173 


stroma forming cells of the marrow which limits the out- 
put of red cell framework. There is plenty of pigment 
material (an excess in fact) as evidenced by the high 
color index or the saturation of the red cell with hemo- 
globin. Wherever we meet with a high color index we 
should suspect some deficiency in stroma construction or 
some over-production of body pigments including hemo- 
globin. Conditions of malignancy, for example, with the 
hematology of pernicious anemia should yield informa- 
tion of value when examined with these points in mind. 
Nothing in this paper should be construed as minimizing 
the importance of stercobilin analyses for we are confi- 
dent that such information is of great value. High ster- 
cobilin figures may be a very valuable diagnostic aid in 
obscure cases of pernicious anemia, as claimed by Hans- 
man and Howard. That these figures indicate a corre- 
sponding destruction of red cells may be doubted and an 
overproduction of pigment may be a safer assumption.” 
McMaster and Haessler (421) showed however that 
stroma building material was practically inexhaustible. 
The explanation of the pigmentary disturbances may 
yet fall back, in a general way, to the theories of the ear- 
lier observers of the bone marrow, particularly Cohnheim 
(123) and Ehrlich (163) who conceived of the anemia as 
primarily a disease of this tissue. Faulty nuclear matura- 
tion on the part of the youngest red blood cells is a func- 
tional diagnosis fraught with exceedingly great possibili- 
ties, especially, if, as Whipple (645) has been impelled to 
suggest, the reticulo-endothelium may be concerned with 
hemoglobin construction, and, too, as Doan et al. (150) 
strongly suggest, the reticulo-endothelium gives rise to 
the megaloblasts. If such conceptions could be established 
as facts, or even as probabilities, then it would not be 
beyond the pale of sanity to conceive of disturbed pig- 
ment metabolism, disturbed blood formation, and all other 
blood abnormalities of pernicious anemia, as due funda- 


174 PERNICIOUS ANEMIA 


mentally to a diseased condition of the reticulo-endothelial 
tissue. 

(3) Physical and chemical changes in the blood. The 
blood when seen in quantity has a much redder appear- 
ance than the number of cells would lead one to expect, 
because of the large average cell size. When a drop of 
very anemic blood is allowed to absorb upon a piece of 
bibulous paper, it shows, after drying, a central red area 
surrounded by a faint pinkish zone. Cabot (90) denoted 
this as a characteristic of the blood. 

The serum in severe cases is of a buttercup yellow 
color, due to the staining with bilirubin in contrast to the 
straw-color of normal serum. 

The specific gravity of the serum is decreased, and that 
of the red blood cells is normal, with a resulting decrease 
in the specific gravity of the whole blood (222). 

The refraction is low probably owing to the reduction 
in serum globulin (222). 

The freezing-point is practically normal in the majority 
of cases (222). 

The specific electrical conductivity of the plasma has 
been found normal (77). 

The patients occur in all four of the iso-agglutinin 
groups. In other words, all the groups may suffer from 
the disease. Ashby (19) noted that fifty-two per cent of 
the cases at the Mayo Clinic at one time were of group 
IV. Oscar B. Hunter (288), from among thirty-eight 
cases, found thirty-four of group II, three of group IV, 
and one of group III (Moss classification). After repeat- 
ed transfusions, some cases develop antagonistic lysins 
and agglutinins against all donors. Occasionally cases 
have been encountered, as among other diseases, exhibit- 
ing the phenomenon of auto-agglutination (122). 

The serum has been shown by Clark and Evans (115, 
116) to possess decreased protective power against hemol- 
ysis by saponin. This is especially true of serum from 
severe cases. 


THE BLOOD SYSTEM WAS 


The red blood cells show a decreased fragility to hypo- 
tonic salt solutions. This is marked in some cases, moder- 
ate in others and absent in a few. As a rule however, 
pernicious anemia cells are more resistant to hypotonic 
solutions than are normal cells. Green (235) has shown 
that this is not a sign of strength but rather of injury. He 
showed that washed normal red blood cells, after pre- 
liminary treatment with pernicious anemia serum, show 
the same increased resistance. He showed also that wash- 
ed normal red blood cells, after treatment with castor-oil 
soaps, showed, before liberation of their hemoglobin, the 
same increased resistance to hypotonic solutions. Eryth- 
rocytes may give up salt, upon injury, without releasing 
hemoglobin. This egress of salt raises the tonicity of the 
environment. The “increased resistance” is therefore due 
to an inability of the cell to maintain an osmotic difference 
from the surrounding solution because of greater perme- 
ability of the cell wall to the contained salts. Green sus- 
pects that this injury is caused to normal cells by per- 
nicious anemia serum, and may be due to a hemolytic 
agent, the condition of injury constituting a phase pre- 
liminary to hemolysis. 

The total volume of the blood has been repeatedly de- 
termined, by different methods, and always found low or 
normal, but usually low. Lindeman (378) found the blood 
volume from 1600 to 4200 cubic centimeters, or from 
2.4 to 5 per cent of the body weight, as compared with 
Keith, Rowntree, and Geraghty’s normal figure of nine 
per cent of the body weight. Lindeman’s method (377) 
was based on the transfusion of a known amount of un- 
diluted blood, and is apparent from the following for- 
mula: 

If x = initial volume of patient’s blood, 

a = percentage of red blood cells in initial volume, 
b = volume of blood introduced, 
c = percentage of red blood cells in vol. introduced, 


176 PERNICIOUS ANEMIA 


1 = final volume percentage of red blood cells; 
then 
xa -Fibe==1 (Fb bp) 
xa + be=Ix + Ib 
xa — lx = lb — be 
x =Ilb—be 


a—l 
Denny (139) employed, as the basis of his method, 
the oxygen capacity of the patient’s and donor’s blood, 
using the Van Slyke blood gas pump for making the oxy- 
gen determinations. Formula: 
If A = oxygen capacity of patient’s blood before trans- 
fusion, 
B= oxygen capacity of patient’s blood after trans- 
fusion, 
C= oxygen capacity of citrated blood given, 
Q = quantity given in cubic centimeters, 


Boe 


From nineteen determinations in ten cases of perni- 
cious anemia Denny found the blood volume reduced in 
all but two cases. The plasma volume remains essentially 
normal, the decrease in total volume being due to loss 
of cell mass. The cases showing normal total volume had 
a high plasma volume. There is no noticeable relation 
between the severity of the disease and the decrease in 
total volume. As Lindeman, Minot and others have re- 
marked, there is reason to believe that the low total blood 
volume intensifies many of the symptoms of the disease, 
such as fatigue, dyspnoea and dyspepsia. Ashby (20) 
could detect a relationship betwen the throbbing sensa- 
tions and ringing in the ears (tinnitus) and the low blood 
volume for, with one exception, these symptoms disap- 
peared with the establishment of a blood volume of 57 
cubic centimeters for each kilogram of weight. She also 








then Volume = 


THE BLOOD SYSTEM 177 


observed that patients who were in the worse condition 
at the beginning of treatment had the lower blood volume. 
She believed that if a patient’s blood destroying mechan- 
ism would tolerate an increase in the red blood count with 
a stationary or even compensatory falling plasma volume, 
it would be of advantage, but that if his blood destroying 
mechanism was so sensitive that it would not permit much 
increase in the level of the blood count, then the increase 
in plasma volume attending transfusion would be help- 
ful by causing a total increase in corpuscular content 
without greatly raising the red blood count. Changes in 
the patient’s blood volume may so influence the blood 
count as to give an erroneous impression of the total blood 
cell content of the circulation. 

Keith (333) also found the blood volume either normal 
or reduced in pernicious anemia and other chronic ane- 
mias, although in chronic leukemia the blood volume was 
almost invariably increased. He employed the dye method 
of Keith, Rowntree and Geraghty. 

Lorrain Smith froma study of blood volume by the car- 
bon monoxide method, concluded that a gain in weight 
under treatment with no improvement in the hemoglobin 
level was an unfavorable sign and indicated a dilution of 
the blood and consequent escape of serum into the tissues. 

The average volume of the red blood cells in pernicious 
anemia is greater than normal, whereas in simple anemias 
it is less than normal. The average cell volume may be 
determined by the hematocrit or by the use of the visco- 
meter. The term volume index was introduced by Capps 
(100) to denote the volume of the red blood cells relative 
to normal. He measured the mass of corpuscles by centri- 
fuging a small amount of blood in a capillary tube, the 
hematocrit of Hedin. A count of the red blood cells was 
simultaneously made. The percentage by volume of the 
cells divided by the number percentage of the cells is the 
volume index. 


178 PERNICIOUS ANEMIA 


While the high color index in pernicious anemia in- 
forms us that the average red blood cell contains more 
than a normal amount of pigment, it does not inform us 
whether there exists a higher than normal concentration 
of pigment per unit of stroma material. Herz (269) tried 
to express this latter point by the use of the term “specific 
hemoglobin content”, and Rossdale (535) suggested the 
term “volume-color index.’ A simpler term is suggested 
by Haden, viz., saturation index. Haden (245) in work- 
ing out very accurate figures for the saturation-index 
employed the technique suggested by Hooper, Smith, 
Belt, and Whipple for determining the mass of the red 
blood cells, and the ferricyanid method of Haldane (Van 
Slyke’s adaptation) for estimating the hemoglobin. 


hemoglobin percentage 


The saturation index ={———_______"—__ 
volume percentage of cells 


The following table shows the typical volume, color 
and saturation indices in normal individuals. 


TABLE 16 
Blood indices in normal person (Haden). 


Oo oA HO) te B= iey S 
wei 06 BBS O88 2 y 5g ey 
a goo) ee 2% che) ce: 
Me . e Whe Ea SA OG aH 
I. 2 SEN es a5 uv) 
4.99 100 101 1.00 1.01 1.01 
4.98 102 104 1.02 1.04 1,02 
5.15 104 106 1.01 1.02 1.01 
5.28 104 103 0.99 0.98 0.99 
4.80 99 97 1.03 1.01 0.98 
4.20 83 84 0.99 1.00 1.01 
4.56 90 90 0.99 0.99 1.00 
5.20 98 103 0.95 0.99 1.05 
4.87 99 97 1.02 0.99 0.97 
4.97 98 99 0.99 1.00 1.01 


The next table shows the typical blood indices in cases 
of simple anemia due to various causes: 


(in millions 
per c. mm.) 
Percentage by 


Red blood cells 
volume of 


red blood cells 


& 
ire) 


THE BLOOD SYSTEM 


TABLE 17 
Blood indices in simple anemias (Haden). 


Hemoglobin 
(in per cent) 


ow 
Sa 


47 


+ Volume index 


Che aS See ola 
NSASBOH YS 
BnSssQ RES 


0.73 


Color index 


ORS 
five} 
£NS 


0.83 
0.70 
1.00 
0.45 
1.02 
0.62 
0.59 


Saturation 


Diagnosis 


178 


Carcinoma stomach 


Chronic nephritis 


Banti’s disease with gas- 


tric hemorrhage 


Subphrenic abscess 
Diffuse carcinomatosis 


Pyelonephritis 
Syphilis 


Acute gastric hemorrhage 


Hemorrhoids 
Chronic intestinal 
hemorrhage 


The next table shows the same indices in fifty succes- 
sive cases of pernicious anemia. 


Red Blood Cells 
(in millions 
per c. mm.) 


of Red 
Blood Cells 


Percentage 
by Volume 


TABLE 18 
Blood indices in 50 cases of pernicious anemia (Haden). 


Hemoglobin 
(in per cent) 


Volume 
Index 


CN ee 
ROopNAD DD AW 
ASX BSRHFSSBLSESERSR 


UN WWW! 


Color 
Index 


Oe ee pp 
NON OH WNHH RAN BOUNNH BPH 
SSRSUBSKRRSSELRANKSE 


Saturation 
Index 


180 PERNICIOUS ANEMIA 


1.39 37 37 1.32 32 1.00 
1.39 42 37 1.50 SZ 0.85 
1.39 44 39 1.56 1.39 0.88 
1.42 42 43 1.51 1.57 1,02 
1.48 46 46 1.53 153 1.00 
1.52 49 49 1.61 1.61 1.00 
1.58 46 44 1.45 1.39 0.96 
1.61 39 37 1.22 1.16 0.93 
1.62 42 43 1.31 1.34 1,02 
1.64 46 46 1.39 1.39 1.00 
1.65 42 36 1,27 1.09 0.86 
7S 48 38 1.38 1.10 0.79 
e755 46 38 1.38 1.10 0.79 
1.80 48 39 1.33 1.08 0.82 
1.87 56 51 1.50 1.36 0.91 
1.87 51 51 1.36 1.36 1.00 
1.88 63 59 1.68 1.57 0.93 
1.99 56 52 1.40 1.30 0.93 
2.10 58 55 1.35 1.30 0.96 
2.18 57 57 Lai 1.31 1.00 
2.23 75 72 1.69 1,62 0.96 
2.27 81 42 1.77 0.93 0.53 
2.33 62 58 1.33 1.24 0.94 
2.36 68 64 1.45 1.36 0.94 
2.41 74 74 157 1.54 0.98 
2.60 61 49 117 0.94 0.80 
2.60 75 65 1.44 1.25 0.99 
2.79 69 65 123 1.16 0.94 
2.88 85 77 1.46 1.33 0.91 
2.93 79 82 1.35 1.39 1.03 
3.16 92 82 1.46 1.30 0.90 
3.33 81 80 1.20 1.20 1.00 
3.44 75 71 1.09 1.03 0.95 
Av. 
1.71 47 44 1.41 1.29 0.92 


The next table compares the indices in normal blood 
and in that of pernicious and simple anemias. 


TABLE 19 
Blood indices in various conditions compared (Haden). 


ae oe 

oO A= ees) es 

O Sea ° UO & aot 

Bee Ses 38 8 

[op Te ee SS aie) vo » 

aa] Bu § oPan] Q © iS tal uM g * 

u-E oO 358 go 2 Rom) Bo 

goaclg ds Se Be Hz 

4 way CoO a OR Nis 

4.74 95 95 1.00 1.00 1.00 Average 52 normal men 
and women 

1.71 47 44 1.41 1.29 0.92 Average 50 cases per- 
nicious anemia 

3.40 63 55 0.94 0.81 0.86 Average 47 cases sec- 


ondary anemia not due 
to hemorrhage 

0.80 Average 7 cases hemor- 
rhagic anemia 


w& 
on 
N 
wn 
wn 
Oo 
N 
N 
Oo 
ON 
Lie) 


THE BLOOD SYSTEM 181 


It will be seen that in normal blood all the indices are 
always 1.0, that in simple anemias all the indices are less 
than 1.0, and that in pernicious anemia while the volume 
and color indices are increased, the saturation index re- 
mains practically normal. Haden (525) and Piney (499) 
have both pointed out that the real size of the red blood 
cells is better judged from the volume index than from 
the color index or from the graphic method of Price- 
Jones. The defect of the graphic method (diameter-inci- 
dence curves) is shown in family hemolytic jaundice 
where the cells look small because they are globular in 
form but the average size, as determined by the hemato- 
crit or the viscometer, is actually large. Viscometric 
measurements, Piney asserts, show a high average volume 
for the red blood cells in pernicious anemia, persisting in 
remissions. Haden finds that a plus volume index is 
present even in very early cases of pernicious anemia be- 
fore other changes are apparent. For this reason he be- 
lieves that a plus volume index associated with achlor- 
hydria is practically pathonomonic of pernicious anemia. 

Mills (436) has shown that the size of the red blood 
cells in anemias may undergo considerable hourly varia- 
tions, and he believes that in a certain percentage of cases 
a definite relationship exists between the percentage of 
hemoglobin and the cell surface. Rabinowtch (511) indi- 
cated a similar relationship in normal blood. 

While most reports on the coagulation time in perni- 
cious anemia indicate a delay, the studies of Drinker and 
Hurwitz (155), as well as those of Minot, Denny and 
Davis (445) show that the coagulation of the blood is 
but slightly altered. Prothrombin is slightly diminished 
in all cases, a fact probably associated with reduction of 
platelets and degrees of bone-marrow aplasia. Bleeding 
time was always long. Antithrombin and fibrinogen were 
always consistently normal. Blood transfusion did not 
affect the latter two factors although it tended to cause a 


182 PERNICIOUS ANEMIA 


slight transient rise in prothrombin. Hurwitz and 
Drinker (313), from a study of the coagulation factors 
in experimental aplastic anemia from benzol poisoning 
concluded that the bone marrow played no part in the 
production of antithrombin and was not essential to the 
production of fibrinogen, and that a minimum amount of 
myeloid tissue was sufficient to maintain the quality of 
the prothrombin above a dangerous level. 

From this account of the many changes in the blood 
system it must be evident, at least, that the respiration of 
the bodily tissues generally must suffer from the lack of 
red blood cells and hemoglobin. This functional deficiency 
is partly overcome by circulatory compensation. In this 
connection the recent remarks of Graham (215) are 
quoted: “The tissues receive their oxygen supply not 
directly from the hemoglobin but from that dissolved in 
the plasma. The amount of oxygen present in the plasma 
is dependent upon the percentage saturation of the hemo- 
globin with oxygen and not on the amount of hemoglobin 
present. In cases of chronic anemia with varying percen- 
tages of hemoglobin even as low as 30, the ratio of the 
oxygen content of the arterial and venous bloods remains 
constant, irrespective of the percentage of hemoglobin. 
These physiological facts afford an explanation for the 
clinical observation that patients suffering from perni- 
cious anemia with a hemoglobin of 30, and a red blood 
count of 2,500,000 are very often able to do moderately 
heavy work without distress.” 


CHAPTER VII 
METABOLIC OBSERVATIONS 


Abnormalities in the digestion, absorption and ultimate 
fate of the organic and inorganic food constituents, 
energy metabolism, blood enzymes, and the effects of 
several forms of treatment on a patient suffering from 
pernicious anemia, afford a heterogeneous mass of data 
which, in the absence of a well-demonstrated funda- 
mental process, cannot be presented with satisfactory 
perspective, but must be described in a somewhat serial 
manner. 

It seems increasingly possible that the causative pro- 
cess in this disease is of a metabolic nature. It may con- 
sist in the perversion of metabolites necessary to the nor- 
mal function of the hemopoietic and nervous systems par- 
ticularly. To inquire whether such a perversion concerns 
proteins or lipoids, and whether it results from digestive, 
assimilative or endocrinous abnormalities would be still 
farther afield from our present task. It might appear 
that in the chronic hemolytic anemia of pregnancy and 
the severe anemia of dibothriocephalus infection a similar 
metabolic condition was reached. While there is no ex- 
plicit proof that such is the case, the nitrogen partition 
in the first of these two diseases was found similar to 
that obtaining in pernicious anemia (223), and everyone 
is conscious of similarities in the cachexias of syphilis, 
gastric cancer and pernicious anemia. 

The digestion and absorption of food. The nitrogen 
lost in the feces is above normal (331). Intestinal putre- 
faction is denoted by increased elimination of ethereal sul- 
phates (331). The duodenal fluid contains a normal 
amount of proteolytic enzymes (31, 414). 

Of the fat eaten, 72 to 89 per cent is utilized (223). 
There is no evidence of the intestinal formation of abnor- 


[ 183 ] 


184 PERNICIOUS ANEMIA 


mal amounts of unsaturated fatty acids (223). The duo- 
denal fluid contains a normal amount of lipase (331, 
414). 

There is no reason to suppose that achlorhydria harm- 
fully interferes with protein or fat digestion in perni- 
cious anemia any more than in cases of uncomplicated 
achlorhydria. 

Studies of the nitrogen metabolism have indicated, in 
general, that difficulty exists in establishing a nitrogen 
balance (230, 231, 417, 438, 449, 492, 533, 616). Mosen- 
thal (454) as well as Peppard (491), following the thera- 
peutic suggestions of Barker and Sprunt (25), gave 
forced feedings with high protein and caloric diets, and 
found that favorable nitrogen balances could thus be 
readily obtained. Gibson and Howard (223) applied to 
pernicious anemia for the first time, specifically and in- 
tentionally, the high-iron diets which had been used ex- 
perimentally by Whipple et al. to produce blood regener- 
ation in dogs rendered anemic from hemorrhage. The 
diets employed by Gibson and Howard produced favora- 
ble nitrogen balances as a rule. Such favorable balances 
were accompanied by favorable iron balances. But nega- 
tive nitrogen balances and coincident iron retention 
obtained in some cases. 

The nitrogen partition in pernicious anemia has been 
found, on the whole, but not constantly, to show the fol- 
lowing characteristics—low urea nitrogen, moderate am- 
monia nitrogen, and high uric acid nitrogen (144, 223, 
438, 533, 601). Gibson and Howard (223) found that 
blood transfusion increased the total N excretion, and 
the urea, uric acid and creatinine nitrogen figures, for a 
period of at least two days. Weicksel (640, 641, 642) 
found after transfusion, increase of total N, and uric 
acid nitrogen, gradually subsiding to pre-transfusion 
levels after five days. He attributed the increase of both 
to the destruction of the transfused blood cells. 


METABOLIC OBSERVATIONS 185 


Minot (438) noted, after splenectomy, a more favor- 
able nitrogen balance and a rise in the urea nitrogen 
which had previously been very low. Pepper and Austin 
(492) noted after splenectomy a positive N balance re- 
placed, 14 days after operation, by increased nitrogen re- 
tention and a return to the pre-operative balance after one 
month; and the uric acid excretion, though never exceed- 
ing the normal limits, showed a decrease of 22 per cent 
after operation. Dennis (144) found no changes in the 
nitrogen partition in two cases subjected to splenectomy. 
Kahn and Barsky (331) note a considerable increase in 
the oxyproteic acid nitrogen of the urine. Becker (35) 
usually found a positive N balance. 

Following transfusion and splenectomy, Pepper and 
Austin (492) noted a more favorable N balance and a fall 
in the uric acid nitrogen. 

The iron balances were found by Gibson and Howard 
(223) to follow consistently the gain, the stationary state, 
or the fall in the blood cell counts and hemoglobin percen- 
tages, and to be apparently uninfluenced by the deposition 
in, or discharge of, stored iron from the tissues. The use 
of their high-iron diet caused favorable balances in eight 
cases, approximate equilibrium in two cases and a nega- 
tive, though improved, balance in one case. Coincident 
betterment of the blood picture occurred. Two cases in 
which less favorable figures were obtained were being fed 
on somewhat higher amounts of fat, and these observers 
suggested that further investigation of fat ingestion 
should be carried out. Pepper and Austin (492) noted 
increased iron elimination in the stool following splenec- 
tomy, as did Gibson and Howard. 

More work is required on the purine metabolism, in 
view of the high uric acid N figures, and the benefits de- 
rived from feeding glandular organs. 

The perennial interest in the fat metabolism in perni- 
cious anemia arose in the first place from the investiga- 


186 PERNICIOUS ANEMIA 


tions of Schaumann (555), Tallquist (606), and Faust 
(192, 194) upon the cause of dibothriocephalus anemia. 
These investigators found that the proglottides of this 
worm contained cholesterol oleate as 10 per cent of their 
solids. Cholesterol oleate was regarded as the causal fac- 
tor because it was hemolytic im vitro. However, it was 
practically harmless on parenteral injection. The ground- 
up worm-bodies were hemolytic both im vitro and in vivo. 
Schwartz (568) has somewhat recently shown that in the 
cases of anchylostoma, trichuris and the anoplocephaline 
cestodes, the strong hemolysins are alcohol soluble sub- 
stances bound to the worm tissues and that freeing these 
fractions from ether-soluble substances renders them 
more hemolytic. He therefore abrogates the importance 
of oleic acid in worm anemia. 

Adler (4) in 1913 produced blood crises in rabbits by 
feeding non-toxic amounts of unsaturated fatty acids. 
Joannovics and Pick (324, 325) showed that subacute 
poisoning with toluylendiamin caused a tremendous in- 
crease of oleic acid in the liver and marked hemolytic 
anemia. They also demonstrated that in acute yellow 
atrophy of the liver and in phosphorus poisoning, either 
experimental or clinical, active hemolysins could be ex- 
tracted from the liver and the blood showed large quan- 
tities of fatty acids. They considered that the unsaturated 
fatty acids of the liver were the hemolytic agents extract- 
ed from the liver. 

From several sources, chiefly from the work of Beumer 
and Birger (46, 47) and of Berger and Tsuchiya (43) 
has arisen the conception of a toxic lipoid developed in the 
intestinal mucosa as the result of (unproved) constitu- 
tional abnormality of this tissue. Several attempts have 
failed to isolate from this mucosa any hemolytic substance 
notably different from those which occur in normal muco- 
sae, or other tissues. McPhedran (425) has shown that 
in chemical poisoning no fatty acids more hemolytic than 


METABOLIC OBSERVATIONS 187 


oleic acid are produced. Seyderhelm (571) did for the 
bothriocephalus proglottis what Schwartz did for other 
worms,—showed that the active hemolytic agent was an 
alcohol-soluble substance bound to the tissues, and not the 
lipoid. Feeding oleic acid to young dogs caused, in Beu- 
mer’s (45) hands, no anemia. 

In spite of these negative results, interest in the sub- 
ject has persisted. Eppinger (173) with King (336), as 
well as Medak (426), reported increased total blood fats 
with high value for iodin numbers, and decreased choles- 
terol in the blood of pernicious anemia. The investiga- 
tions of others has confirmed the low cholesterol but not 
the increase of unsaturated fatty acid. The work of Bloor 
and MacPherson (51), Csonka (136), Dennis (143), 
Kip (338), and others has shown that in severe anemic 
phases of the disease the blood cholesterol is greatly re- 
duced. This is probably a result of the anemia since a 
similar reduction occurs in severe simple anemias. Such 
an explanation harmonized with the theory that choles- 
terol is an intermediary product in fat metabolism, to 
which the red blood cells are vitally related. The chief 
reason for interest in cholesterol is its anti-hemolytic 
qualities; but its decreased concentration in the blood 
cannot, unfortunately, be used as an argument for the 
presence of a hemolytic agent. 

Csonka (136) could attach no specific significance to 
fatty acids as agents of blood destruction. The attempt of 
Brinkman and Szent-Gyorgyi (70) to find in linolenic 
acid the cause of normal and pathological hemolysis was 
not convincing. As Csonka (136) remarks, unsaturated 
fatty acids constitute 48 per cent of the fatty acid con- 
tent of normal blood, and since such acids exist in normal 
blood and in pathological but non-anemia conditions as 
well, they cannot be regarded as bearing any primary 
relationship to abnormal blood conditions. 


188 PERNICIOUS ANEMIA 


King (336) and Bloor (51) found the total blood fat 
high but Gibson and Howard (223) did not. In fact these 
latter investigators found the blood and plasma fat very 
low in severe anemia with increase as the blood improved. 
Dennis (143) had found the blood fat low in two cases. 
Although Gibson and Howard found the blood fats low, 
they were associated with higher iodin numbers, although 
the total amounts of iodin absorbed were small. They con- 
firmed Bloor’s finding that the blood cholesterol fluctu- 
ates directly with the blood count. They found no substan- 
tiation for the supposition that unsaturated fatty acids 
cause the anemia. 

There exists no proof, therefore, that the fat metab- 
olism in any way enters causally into the pathogenesis of 
pernicious anemia. The preservation of the subcutaneous 
fat layer, sometimes even in cachexia and under condi- 
tions of virtual starvation stands, nevertheless, as a 
somewhat distinctive feature of the disease. Suboxida- 
tion exists, as evidenced by the increased neutral sulphur 
fraction of the ethereal sulphate excreted. 

The carbohydrate metabolism is apparently not affect- 
ed. Adams (3) reported three cases of diabetes in asso- 
ciation with pernicious anemia at the Mayo Clinic over a 
period of five years, during which time 1000 cases of per- 
nicious anemia and 2000 cases of diabetes were encoun- 
tered. Schumann (564) reports a case of the two diseases 
associated, in which glycosuria disappeared following the 
use of insulin, the patient dying of pernicious anemia. In 
spite of Johnson’s (326) contention that a high blood- 
sugar level attends very severe anemia, the reports of 
others (434, 52) make it clear that no important dis- 
turbance of the sugar metabolism occurs. 

Certain chemical alterations in the blood are found. The 
blood proteins are reduced in the blood as a whole, de- 
pending partly upon the numerical reduction of corpus- 
cles and partly upon a reduction in the serum protein 


METABOLIC OBSERVATIONS 189 


(46, 331, 497). The individual corpuscles show an in- 
crease in protein corresponding to their increased average 
size (46). The serum albumin is normal but the serum 
globulin is very much decreased (46). 

The blood as a whole shows a lowered total nitrogen 
because of the reduction in corpuscles, but the plasma 
shows either normal or high total nitrogen values (497). 
The relation of the total whole blood nitrogen to the total 
plasma nitrogen constitutes the nitrogen index, a figure 
which will decrease in proportion to the severity of the 
anemia, and might have some prognostic value (497). 
The only nitrogen fraction increased in the blood is the 
creatinin (331), due more to a destructive process present 
in the body than to any failure of the kidney to eliminate 
this substance. Others have found urea and especially 
the amino-acids increased (222). 

Disturbance of the acid-base balance of the body is in- 
dicated by the reduced COz combining power of the 
plasma and an increased hydrogen ion concentration of 
the plasma. In three cases examined by Kahn and Barsky 
(331) the COs of the alveolar air was 4.4, 4.7, and 4.6 
respectively. 

Reference has already been made to the absence of the 
alkaline tide in the urine. 

As Blankenhorn has shown, bile salts are frequently 
found in the blood, either alone or associated with bili- 
rubin. This suggests that the liver is implicated in the 
disease process but to what extent is not known. Liver 
function (331) has been referred to in the last chapter. 

The mineral content of the blood is slightly altered. 
The ash is increased through increased calcium and mag- 
nesium (331). The serum contains more potassium than 
normal (46). The total phosphorus content of the whole 
blood is roughly parallel to the hemoglobin in all persons 
in whom the values of the total phosphorus in plasma and 
corpuscles are within normal limits. This parallelism is 


/ 


190 PERNICIOUS ANEMIA 


due to preponderance of phosphorus in the red blood cor- 
puscles. Immature red blood corpuscles probably contain 
more phosphorus than adult ones. Buckman et al. (79) 
give the following figures for phosphorus in pernicious 
anemia blood: 

TABLE 20 


Phosphorus in blood of pernicious anemia (Buckman, Minot, 
Doland, and Weld). 
HPO am 100 ce. oF 


m2 

29 

Ke oO 

° ae , a “5 
S ) 8 3 : Bo 
a y F) a 5 2 ve 6 SE 
a of) =: ° as) “a 4 = 
S) < A = A, S eo © ae 
1 58 P.A. 9.8 LAS a 0.8 20 9.6 
2 21 P.A. 13.1 13:2 12.0 1.4 30 12.9 
3 50 P.A. 11.9 12.1 8.3 13 30 8.0 
4 73 P.A. 10.2 10. 9.5 1.8 35 21.3 
11 55 P.A. 12.6 13.6 6.9 1.0 55 14.8 
12 51 PaaS 13.6 14.8 12 1.7 55 16.4 
13 39 REAG 1355 14.0 11.9 2.8 55 29.3 
14 50 P.A. 14.2 13.7 15.8 2.6 60 25.9 


Haden (246) could find no positive evidence of a dis- 
turbance of chloride metabolism, although a few cases 
showed a low chloride content of the blood. The chloride 
level of the blood bore no relationship, in other anemias, 
to the free hydrochloric acid of the gastric juice or to the 
volume index of the red blood cells. 

Rioch and Cameron (529) found in the active stages 
of the disease that the red corpuscles contained less 
chloride than normal but that the plasma chloride is rela- 
tively constant and normal throughout. They emphasize 
the importance of estimating the chloride ion in the gas- 
tric secretion since, in their experience, this ion, as well 
as HCl, was absent. 

Major (396) found so little urinary chloride excretion 
as to suggest a retention. The ingestion of from 6 to 20 
grams of NaCl by five patients daily produced no increase 
in chloride excretion, although these cases gave no evi- 


METABOLIC OBSERVATIONS 191 


dence of renal disease. Major suggested that the retention 
might bear some analogy to the retention seen in lobar 
pneumonia and in certain cases of intestinal obstruction. 
Haden (248) has likewise emphasized the resemblance of 
the chloride metabolism in pernicious anemia and intesti- 
nal obstruction. 

The catalase content of the blood was investigated care- 
fully by Krumbhaar and Musser (349), and was found 
diminished because of reduction of red blood cells. They 
regard the reduction in catalase which follows splenec- 
tomy as due to the transient anemia resulting. The cata- 
lase index is the number of cubic centimeters of oxygen 
liberated, divided by the number of million red blood cor- 
puscles. Thus :— 

No. of cc. oxygen liberated by 0.1 cc. blood in 15 min- 

utes is 37 
No. of millions of red blood cells per cubic millimeter of 
blood is 0.92 

Catalase index is 40. 

From their tables, the following average figures are 
quoted : 

TABLE 21 


Catalase index in various conditions (average results) (Krumb- 
haar and Musser). 
Cc. Oxygen R. B. C. per Catalase 
C. Mm. 


Condition liberated Index 
Pernicious anemia 

(O)\cases) jyiees tia Sees 45.3 1,480,000 28.6 
Other anemias 

Gilt eases) F 20). VIET es 92.5 3,322,000 28.0 
Non-anemia (5 cases) 

Normal’ (4) cases) 22.00.52 164.1 5,015,000 32.7 


(Strauss and Rammelt’s (602) catalase index was the 
number of grams of H2Oz liberated from 30 cc. of 1 per 
cent H2O2 by 1 cc. of a 5: 1000 blood solution, divided 
by the number of millions of red blood cells in this 1 cc. of 
diluted blood. On this basis, normal blood has a catalase 
index of 4.6; that of secondary anemia, 4.8; polycy- 


192 PERNICIOUS ANEMIA 


themia blood 3.2; and the blood of pernicious anemia, 
8:5). 

Becker et al. (37) found increased amounts of blood 
phenols, as well as free phenols in the blood of pernicious 
anemia. 

The blood serum of pernicious anemia is said to have 
less inhibiting effect on pepsin activity than has normal 
serum, although it is usually considered that in anemias 
the anti-enzymatic activity of the serum is increased. 

Simon (580) found in 6 out of 14 patients the presence 
in the serum of a lipase which differed from normal se- 
rum lipase in being resistant to the action of atoxyl. This 
atoxyl-resistant lipase is destroyed by quinine, as are the 
lipases of the sera from all diseases except those with 
jaundice of hepatic origin. The origin of this atoxyl- 
resistant lipase is obscure but it is presumably derived 
from the pancreas. Simon found it also in cases of pan- 
creatic disease. The writer (135) was able to confirm the 
presence of this lipase in only 6 of 36 cases of pernicious 
anemia, although the sera used were usually more than a 
day old; in one of the 36 cases a cholesterinase could be 
demonstrated as well as a tributyrinase. The atoxyl-resis- 
tant lipase of Simon probably has no great significance in 
this disease. 

Stephan (591) claims to have found a proteolytic fer- 
ment in pernicious anemia serum, derived, he believes, 
from the reticulo-endothelial cells, and constituting one 
argument for his hypothesis of overactivity of these cells 
as the cause of the disease. 

The organism suffering from pernicious anemia is 
capable of forming agglutinins to B. typhosus and B. 
paratyphosus, A. and B. (280). 

Compensation for diminished hemoglobin content of 
the blood is accomplished by increased pulse rate, in- 
creased cardiac output per beat, and increased depth of 
respirations which is chiefly of value in filling the right 


METABOLIC OBSERVATIONS 193 


side of the heart (191, 453). Meyer and Dubois (435) 
found the basal metabolic rate but very slightly increased 
in three mild cases but in two severe cases the demand for 
oxygen was from 7 to 33 per cent above the normal 
average. The basal metabolism in pernicious anemia was 
lower than that of leukemia, but higher, as a rule, than 
that of simple anemias. The agreement between the direct 
and indirect calorimetry, as well as the respiratory quo- 
tients, indicates that the basal metabolism of pernicious 
anemia is qualitatively identical with the normal. 

The basal rate, when determined on a series of cases, 
shows no great difference from that of normal indi- 
viduals. Some are a little above, and some a little below, 
normal. Wilson (659) noted a tendency for the rate to 
be low during relapses. 

Tompkins, Brittingham, and Drinker (614) have made 
the most illumninating studies undertaken in connection 
with blood transfusions. A patient with pernicious ane- 
mia shows, after transfusion, an immediate fall in heart 
and respiratory activity, but no immediate fall in meta- 
bolic rate. Some days later, however, the metabolic rate 
invariably falls. Muscular activity reduction cannot ex- 
plain this diminution of energy output. These investiga- 
tors feel that there are two opposing factors operative on 
the metabolism of these patients. (1) There is a tendency 
to increased use of energy, perhaps occasioned by the ab- 
normal and increased marrow activity. (2) There is a 
tendency to decreased use of energy, caused by the patho- 
logical storing of fat not only in fat depots but as infiltra- 
tions in normally active tissues. The use of energy for 
blood maturation is brought to a stand-still by a blood 
transfusion, not all at once, but after a period of days, 
during which adjustment of some sort takes place. 
In other words, blood transfusion neutralizes the stimu- 
lation to blood formation. Hence transfusion really un- 
masks the actual metabolic state of the patient. When 


194 PERNICIOUS ANEMIA 


thus unmasked, the metabolic rate is invariably found to 
be lower than it was before, regardless of its previous 
level. It is of interest that blood transfusion lowers the 
temperature if it has been previously elevated. 

The specific dynamic action of foodstuffs has not, so 
far as we are aware, been studied in patients with this 
disease. 

Mason and Mason (410) noted a depression in the 
metabolic rate following exposure to ultra-violet light in 
certain cases, a phenomenon possibly associated with the 
presence in the skin of bilirubin. 

Kabanow’s (330) sero-diagnosis of pernicious anemia 
has never received very wide recognition. Red corpuscles 
in this disease show an extremely high degree of reversi- 
bility of hemolysis (590). The use of foreign protein 
thereapy frequently does away with diarrhoea and fever 


and may apparently initiate improvement generally (183, 
284, 514). 


CHAPTER VIII 
THE NERVOUS SYSTEM 


Nervous changes were not specifically remarked by 
the earlier observers, because the manifestations, except 
for marked neurotrophic and motor disturbances (which 
are not constant) tend to be largely subjective, and when 
objective, certainly not obtrusive. Addison (5) noted 
fatty changes in a portion of the semilunar ganglion of 
the solar plexus. Biermer (60) mentioned hemorrhages 
in the brain and retina. Little (381) construed most of 
the total general symptomatology as evidence for primary 
involvement of the nervous system, a construction which, 
though periodically revived (266, 390, 581), cannot now 
be sanctioned. Lichtenstern (373) in 1884 reported pos- 
terior column degeneration and pernicious anemia occur- 
ring in two cases diagnosed as tabes dorsalis. It is almost 
certain they were instances of true pernicious anemia. 
Lichtheim (374) in 1887 described a case of severe 
anemia presenting clinically stiffness and weakness of the 
legs, ataxia, parasthesia, and Rhomberg’s sign, and, post 
mortem, marked degeneration of the columns of Goll and 
Burdach, with foci of degeneration in the lateral and 
anterior columns. Lichteheim’s findings not only opened 
up a new aspect of pernicious anemia but stimulated 
neurological investigations in general. 

During the next thirty years, the reports of Putnam 
(504), Dana (137), Stewart (595), von Noorden (625), 
Eisenlohr (168), Minnich (437), Nonne (472, 473), 
Burr (85), Money (451), Taylor (608), Boedeker and 
Juliusberger (53), Russell, Batten and Collier (543), 
Lloyd (382), Colquhoun (127), Klein (341), Bastienelli 
(32), Clark (117), Petren (498), Campbell (97), Duck- 
worth (156), Brown, Langdon and Wolfstein (75), Bil- 
lings (61), Bramwell (65), the Déjerines, Crouzon, and 


[ 195 ] 


196 PERNICIOUS ANEMIA 


Jumentie (140, 141, 142), Cadwalader (93), Schaller 
(550), and many others delineated the spinal-cord changes 
as a type of combined system disease, causing well-recog- 
nized symptoms and signs. Frequently enough, these were — 
taken to constitute a separate disease of the nervous 
system. 

During the past ten years (1917-1927), the report of 
Hamilton and Nixon (253) settled in the affirmative the 
question whether peripheral nerve degeneration occurs. 
Hurst and Bell’s (311) reports on achlorhydria in these 
cases constitute a very strong argument for refusing 
them the status of a disease distinct from pernicious 
anemia. Woltman’s (662) report demonstrated that the 
brain, as well as the cord and peripheral nerves, showed 
degenerative foci. The contributions of Hamilton and 
Nixon and of Woltman are of classical importance in 
pathology and ought to be studied in great detail. 


THE ANATOMICAL AND HISTOLOGICAL CHANGES 


The brain (662) on being exposed is normal in size, 
of a grayish white or pearly white apearance with, usu- 
ally, considerable edema of the pia-arachnoid, and some 
peri-vascular opacity in these membranes. The sinuses are 
usually practically empty. The ventricles are normal in 
size and their walls smooth and glistening. The vessels at 
the base of the brain may show slight thickening and stand 
open when cut, but do not present atheroma. 

The spinal cord appears large, in spite of the degener- 
ative process within it. This is because of the edematous 
nature of the process and the absence of neurogliar 
proliferation (125). 

Hemorrhages of a petechial nature may be found in 
the dura, both of the brain and cord, or in the paren- 
chyma of either, while, exceptionally, a considerable hem- 
orrhage may be found in any of these situations. 


THE NERVOUS SYSTEM 197 


The characteristic lesion, essentially the same in the 
cord and brain, is the so-called Lichtheim plaque, which 
consists, in the early stage of its formation, of a small 
area in the white matter, of a darker and more translucent 
appearance than normal. 

In the cord, the plaque usually makes its first appear- 
ance in the lower thoracic region and in the centre of both 
posterior columns and soon afterward in the centre of 
both posterior columns as well. Later, small areas of 
degeneration may be seen scattered through almost the 
whole of the antero-lateral columns. These by coalescence 
eventually may involve the entire white matter of the 
cord in a degenerative process, the only portion to escape 
being the narrow zone of short internuncial fibres which 
lie next to the gray matter. In its most fully developed 
state, therefore, an almost complete transverse degener- 
ative blocking of the white matter occurs. It is only in the 
early stages or in moderately affected cases that the pro- 
cess is limited to the posterior or to the lateral columns. 
As Collier (125) points out, this annular degeneration 
of the lower thoracic portion of the cord is highly char- 
acteristic and occurs in no other disease. 

Progression upwards and downwards takes place by 
the occurrence of isolated plaques of degeneration in the 
posterior and anterolateral columns, and by extension of 
these and coalescence with areas already degenerated. In 
this way it does not resemble a system disease of the 
spinal cord. The process may extend upwards as high as 
the internal capsule in the pyramidal tract. The trans- 
verse area involved varies from being confined to the 
posterior and lateral columns, or, as previously indicated, 
to involvement of almost the entire white portion of 
the cord. Cavity formation may occur in the cord (34, 96, 
ol, 212); 

Two other types of change may be seen. (1) Secondary 
degeneration of the white columns both upwards and 


198 PERNICIOUS ANEMIA 


downwards from the Leichteim plaques. (2) Retrograde 
changes, tigrolysis, vacuolization, shrinking and neuro- 
phagy in the nerve cells of Clarke’s column and in the 
Betz cells from which the pyramidal fibres originate. 

In the brain (662), the lesions of greatest interest are 
the plaques of degeneration in the medullary substance of 
the cortex, sometimes visible to the unaided eye, and 
equally often to be detected only by microscopic exami- 
nation. These plaques are usually smaller, fewer in num- 
ber, more widely scattered, and less readily enlarged by 
coalescence and secondary degeneration than those in the 
cord. There also occur small round areas about 0.1 milli- 
meters in diameter, most numerous in the medullary por- 
tion of the cortex, giving the appearance of a localized 
edema. Again, the gray matter in the margin of the gyri 
shows pyramidal cells in all stages of degeneration, sur- 
rounded by small areas of partial necrosis. Woltman 
thought these degenerations were caused by the same 
process as produced the plaques in the medullary sub- 
stance. Varying degrees of tigrolysis, vacuolization, 
nuclear swelling, and axonal reaction were observed. 
Satellitosis and neuronophagia were also seen. Woltman 
confirmed the observation of Henneberg that neurogliar 
reaction was practically absent. 

Woltman (662) from a review of the literature, and 
from his own studies, is inclined to attribute the nervous 
lesions to the action of some toxin. Blankenhorn (48) 
has suggested the possible role of bile salts in this connec- 
tion. The spinal fluid has been found negative on bacterio- 
logical and cytological examination (103). 

The mechanism by which degeneration is brought 
about has been the subject of much argument. One theory 
regarded petechial hemorrhages in the nerve tissue as the 
starting point (437). Another regarded those areas 
most liable to degeneration which received the largest 
blood supply and therefore presented the largest expos- 


THE NERVOUS SYSTEM 199 


ure to toxin (401). Another merely reversed the latter 
theory, stating that areas of poorest blood supply would 
suffer most (68). The ‘“‘vascular theory” was abandoned 
because it was shown that hemorrhage did not always 
occur and that vessel changes did not correctly corre- 
spond to areas of degeneration (32, 322, 505, 543). A 
theory was advanced to the effect that the changes found 
in the white matter were secondary and but part of a 
cycle of degeneration which began in anterior horn-cells, 
whether or not these cells gave microscopic evidence of 
injury (539, 610). 

The theory of a true infectious myelitis of dissemi- 
nated type (53) had to be abandoned because of the lack 
of inflammatory reactions. Dana (138) noting that it is 
the peripheral ends of the axones of the pyramidal cells 
and of the posterior ganglion cells that chiefly show the 
destruction, considered this due to the distance of this 
portion of the nerve fibre from its trophic centre. Wolt- 
man (662) considers that lymph stasis is an important 
factor in the production of the Lichtheim foci, since 
plaques so frequently occur around the blood vessels. 

The earliest change is swelling of the medullary sheaths 
over a small area of the white matter (125). The swollen 
sheaths then break up by fatty degeneration, and the 
axis-cylinders become no longer recognizable. The degen- 
erate contents of the swollen medullary sheaths now 
gradually disappears, leaving nothing but the fine con- 
nective tissue of the spinal cord surrounding vacuolated 
spaces filled with fluid, of varying size, some of which 
represent the spaces originally occupied by the nerve 
fibres, but others are formed by the fusion of several 
such spaces (Collier 125). 

Hamilton and Nixon (253) show that marked degen- 
eration may occur in the anterior and posterior roots and 
in the peripheral nerves. 


200 PERNICIOUS ANEMIA 


THE OCCURRENCE OF NERVOUS INVOLVEMENT 

Five ill-defined types of pernicious anemia may be 
recognized, depending upon the time of appearance of 
nervous symptoms: (a) cases with blood changes preced- 
ing the nervous symptoms by some months. This is the 
most common order of appearance, the neurological mani- 
festations not being noted until nine or ten months after 
the establishment of severe anemia. Numbness, pares- 
thesia and motor phenomena may commence just at the 
peak of a first blood-remission. (b) Cases with blood 
changes beginning some months after the inception of 
nervous symptoms. These are the cases in which early 
diagnosis is possible without anemia. They occur, more- 
over, usually in persons over fifty years of age, and the 
anemia is likely not only to begin very suddenly, but to 
run an acute course. (c) Cases in which the blood-system 
and nervous-system changes begin together. The writer 
has seen two cases presenting initially the following find- 
ings: parasthesia and numbness of the extremities, glos- 
sitis, reduction in hemoglobin, greatly disturbed cellular 
morphology but no reduction in the number of the red 
blood cells. (d) Cases with blood changes occurring only 
terminally. These are the so-called “pure’’ examples of 
subacute combined degeneration of the spinal cord, and 
are responsible for the fact that the nervous changes 
were regarded as having an independent existence as a 
generic disease. More careful and prolonged blood exami- 
nations have shown not only that a simple anemia usually 
accompanies these cases, but that, near the end, even if 
for only a period of six weeks, a truly specific anemia 
occurs, not to be distinguished from that of pernicious 
anemia. (e) Cases without blood changes. These are rare 
instances of fulminating cord damage which terminate 
fatally before the blood system has become implicated. 

The nervous system is involved in eighty and six-tenths 
per cent of all cases diagnosed as pernicious anemia (663, 


THE NERVOUS SYSTEM 201 


664). It is therefore somewhat less often involved than 
the blood system (in ninety per cent) and the digestive 
system (in nearly one hundred per cent). These facts, 
coupled with the almost invariable finding of achlor- 
hydria in association with subacute combined degenera- 
tion, bring out the essential unity of the whole Addisonian 
complex, which may be regarded as a triad of system 
changes in which only one system—the digestive—stands 
obliged to change, the other alterations—those of the 
blood and nervous system—being superstructures raised 
upon this basis. 

The nervous system is involved more frequently in 
elderly than in younger patients. 

The occurrence of remissions does not cause improve- 
ment in the nervous manifestation. Some slight disappear- 
ance of numbness and parasthesia may be observed, and 
probably depends on the small margin of recoverability 
possessed by nervous tissue. Foreign protein therapy and 
the administration of kefir and aciduric cultures may, for 
some reason not apparent, bring about some improvement 
of a similar nature. Objective phenomena do not improve 
even in liver-diet remissions. Spontaneous or other re- 
missions seemingly cause but a cessation in the extension 
of the nervous degeneration. In cases of subacute com- 
bined degeneration progressing slowly for years without 
specific anemia, periods of inactivity of the disease may 
be noted, during which the patient feels comparatively 
well. 

Whether specific glossitis occurs in cases of subacute 
combined degeneration without blood change is not espe- 
cially noted in the literature. In the writer’s two cases it 
did not occur. 

It is quite evident that the nervous changes cannot 
be due to the anemia. The occurrence of one without the 
other may indicate a greater susceptibility of the one tis- 
sue to the causal process. The hereditary influence may 


202 PERNICIOUS ANEMIA 


play a part in deciding this, since the familial occurrence 
of subacute combined degeneration has been noted (702). 

The appearance of cord changes in a case already 
showing characteristic blood changes is believed to indi- 
cate an intensification, as well as an extension, of the 
disease process. In the latter half of the disease the degree 
of cord involvement is of considerable prognostic impor- 
tance. A remission is not likely to occur in a patient with 
very marked cord symptoms, or if it should occur, is not 
likely to be very satisfactory. It is for this reason that 
heretofore it was unusual to see a case in good blood 
remission with disabling residual cord change. Such a 
spectacle is becoming commoner since the liver-diet treat- 
ment has been used. As before stated the true condition 
of the patient is ultimately more related to the nervous 
changes than to the blood changes. 


THE SYMPTOMS AND SIGNS OF NERVOUS INVOLVEMENT 


Among the earliest, most persistent and commonest 
manifestations are sensory subjective phenomena—espe- 
cially numbness and tingling. Similar sensations may be 
present in simple anemia when profound, but they may 
occur as the first indications in this disease, frequently 
with little or no anemia. Other parasthesiae are quite 
commonly added—burning, coldness, griping, band sen- 
sations, dead sensations, twisted and cramping sensations. 
These begin ordinarily in the glove-and-stocking areas, 
extending up the legs, in severe cases, even upon the 
trunk where intersegmental division lines may be noted; 
although they may begin in the perineum, skin of the 
head or in the tongue. Girdle sensations occur usually in 
cases developing spasticity. Lightning pains, similar to 
those of tabes, have not infrequently been met and have 
caused suspicion of an abdominal lesion. Dull aching 
pains, sharp, shooting pains and soreness also occur. 


THE NERVOUS SYSTEM 203 


Among objective sensory changes the one of greatest 
diagnostic importance is the diminution or loss of deep 
sensibility in the distal ends of the extremities with little 
or no loss of cutaneous sensibility in the same parts (525). 
Thus we may find loss of joint-position sense, diminution 
or loss of vibratory sense, astereognosis, acro-ataxia, 
proximo-ataxia, ataxia in locomotion, Rombergism, and 
loss of finer coordination of the fingers. The extremities 
may be hyperesthetic to light touch; and the contact of 
objects with the hands and feet may be painful. An intel- 
ligent patient described it as, “a feeling of exaggerated 
sensitivity.” Such hyperesthesia as well as shooting pains, 
sometimes likened to “electricity,” are found usually dur- 
ing periods of activity when the cord symptoms are 
rapidly progressing. During other stages, cutaneous 
hyperesthesia and anesthesia to touch, temperature and 
pain may occur. The special senses show diminished 
activity. 

The motor symptoms comprise muscular weakness in 
the legs, paraparesis, paraplegia, and weakness or paraly- 
sis in the arms, trunk, viscera and sphincters; ataxia in 
locomotion, ataxic paraplegia; spastic and flaccid paraly- 
sis in the legs. The condition of the reflexes depends upon 
the exact nature of the cord involvement in a given case. 

Trophic disturbance is shown in the muscular wasting 
and atrophy and the common occurrence of bed sores. 

The paraplegic signs ordinarily follow after the sen- 
sory changes but may, in exceptional cases, usher in the 
disease. Usually the patient has become only gradually 
consciousness of leg weakness, unsteadiness or incoordi- 
nation, and shows on examination slight rigidity of the 
lower extremities with weakness of certain muscle groups, 
with increased knee jerks, ankle jerks, foot clonus, and 
an extensor type of plantar reflex. 

In some cases, with implication of the lateral column of 
the spinal cord, the knee jerk is diminished or lost, and 
the picture is that of ataxia with flaccid weakness. 


204 PERNICIOUS ANEMIA 


The clinical picture will depend in every case upon the 
transverse and longitudinal extent of cord involvement. 
When the posterior columns are alone involved, as they 
exceptionally are, a fairly rapidly developing paraplegia 
usually results. When the lateral columns are chiefly 
affected, spastic gait, increased reflexes, and some degree 
of paralysis result; when the posterior columns are 
chiefly affected, the tabetic symptoms appear and may 
progress to loss of sphincter control. Usually both col- 
umns are affected, the one more than the other. A rapid 
annular degeneration involving the whole white matter of 
the cord may present the clinical picture of a transverse 
myelitis. 

As the disease advances, paraplegia progresses upwards 
involving more and more of the trunk. Paraplegia may 
eventually become complete with great muscular atrophy, 
and ordinarily with disappearance of the spacticity. The 
paraplegia does not often proceed as high as the upper lim- 
its of the region supplied by the cervical cord enlargement. 

Although sexual impotence may be an early symptom 
in the male, bladder disturbances and loss of sphincter 
control are usually late manifestations. 

An easy excitability of the skin reflexes, remaining 
well through the disease, is highly characteristic. An en- 
tensor type of plantar reflex is usually the first definite 
sign of organic involvement and remains unchanged. 

The deep reflexes usually show an initial increase 
becoming later lost, with development of the paraplegia. 
The reappearance of deep reflexes after being lost indi- 
cates that the lesion was first confined to the posterior 
columns and later attached to the lateral columns. 

A disharmony between the clinical and pathological 
cord findings very often occurs, and is probably explained 
correctly by Hamilton and Nixon (253) on the basis of 
common lesions in the peripheral nerves. 


THE NERVOUS SYSTEM 205 


ALTERATIONS IN THE PSYCHIC FUNCTION 


Quite apart from any definite psychic abnormalities 
which may attend the disease, a certain constitutional 
mental make-up has been noted in these individuals. 
“, . these patients are different in some way from other 
patients: they listen to what you say, they do not argue, 
they raise no objections; they are almost too good” (665). 
They have been regarded as extremely susceptible to their 
environment (31). 

Sometimes the very first manifestation of abnormality 
in cases eventually becoming pernicious anemia is an 
apprehensive neurosis. Langdon (353) went so far as to 
regard this and other premonitory mental states as mani- 
festations of “pre-pernicious anemia.” It required time 
for other alienists to become agreed with Langdon. Wolt- 
man now even suggests that a certain group of mental 
cases are really pernicious anemia without anemia (665). 

The psychic disturbances range from mild depression 
to violent maniacal outbursts (Lurie 388), from indiffer- 
ence, apathy and severe melancholia to irritability, hyper- 
kinesis, delusions and hallucinations. 

Barrett (27, 28) would place the psychotic manifesta- 
tions among the paranoid conditions which are sympto- 
matic of a toxic, organic process affecting the central 
nervous system. 

Sometimes a distinct psychosis, such as manic-depres- 
sive insanity may occur. These patients have, in the 
writer’s experience, usually given evidence previously of 
harboring a psychosis. It is the general experience of 
mental hospitals that these psychoses clear up during re- 
missions and return with relapses. 

Barrett could not regard the cortical organic changes 
found as being of specific type, resembling rather those 
which occur in chronic intoxications. Woltman did not 
regard the brain changes as the cause of the psychic dis- 
turbances but referred the latter to the operation of a 


206 PERNICIOUS ANEMIA 


toxin. Lurie’s autopsies had all shown psychic disturb- 
ance in life, so that the constant finding of cerebral 
lesions did not indicate a causal relationship, which would 
obviously be proved only by negative brain findings in 
all cases without psychic involvement. Woltman, how- 
ever, found just as marked brain changes in cases with 
normal mentality as in those with mental disturbance. 

The coma which usually precedes death, especially in 
cases with definite nervous involvement, ordinarily lasts 
from twenty-four to seventy-two hours. In some cases it 
is a deep coma, the patient never rousing. In other cases 
the lodging of mucus in the pharynx may rouse the patient 
for a moment, even when voices or shaking have failed 
to do so. 

In cases with psychic confusion, coma seems but a 
deepening of the mental clouding, and such patients may 
rouse during the early stage of coma to make some mut- 
tering remark with regard to their favorite delusion. 
Cheyne-Stokes respiration can usually be detected for 
many hours before death, and even before the pulse gives 
any indication of weakening. Woltman regards the coma 
as evidence of the effect of a toxin on the cerebral cortex. 


CHAPTER IX 


CARDIOVASCULAR, RESPIRATORY, GENITO- 
URINARY AND OTHER SYSTEMS 


THE CARDIOVASCULAR SYSTEM 


Combe (128) noted the pale color of the heart at 
autopsy. Addison (5) mentioned the fatty change in the 
heart muscle and remarked on the easily excited pulse. 
Biermer (60) wrote on the cardiac murmurs, bruits in 
heart and great vessels, the clinical resemblance to endo- 
carditis, the occurrence of hemorrhages and the post 
mortem finding of fatty degeneration of the cardiac 
muscle. Most of the earliest observers, including Elliot- 
son (171) were impressed by the cardiovascular findings. 

It is difficult to distinguish cardiac symptoms from 
those due to the anemia. Dyspnoea, weakness, and faint- 
ness are probably to be attributed more to anemia than to 
the heart, especially in the early stages of the disease, 
although in the later stages the cardiac condition assumes 
an undetermined part in their production. 

Pre-tibial edema is not an infrequent occurrence but it 
is not clear in what degree it is to be attributed to the 
heart. There can be no doubt that increased permeability 
of the vessel walls, due to trophic disturbance secondary 
to the anemia, and possibly other unrecognized factors, 
play their parts. Williamson (665) was unable to decide in 
his unusual case of anasarca complicating the disease, what 
factors were most involved, for there were evidences both 
of cardiac insufficiency and impaired vascular vitality. 
Smith (582) noted the infiltration of tissues by serum in 
cases showing gain in weight without blood improvement 
after transfusion, and regarded this increase of tissue 
fluid as frequently indicative of a critical phase, to be 
followed either by improvement or death. The cardiac and 
vascular conditions, as well as the increased filterability 

[ 207 ] 


208 PERNICIOUS ANEMIA 


of the plasma result, at any rate, not only in clinically 
recognizable edema (pre-tibial, pulmonary) but in in- 
crease of the serous fluids, and in mediastinal, perilaryn- 
geal and mesenteric infiltration in some cases (605). 

A moderate thickening of the radial arteries is some- 
times met with, but definite radial sclerosis must be a 
rare finding in this disease. The vessels at the base of the 
brain are sometimes moderately thickened but atheroma 
has not been observed (662). 

The widespread extravasations noted first by Biermer 
(60) were attributed by him to vascular weakness al- 
though the functional purpura which exists must be taken 
very thoroughly into consideration in this connection. 
Punctiform hemorrhages may occur in the retina, men- 
inges, brain surface, serous membranes, gastric mucosa, 
urinary and gall bladders, and pancreas. Intestinal hem- 
orrhage, sometimes of a severe character, is not really 
uncommon. Metrorrhagia, hematemesis and epistaxis 
also occur. 

The capillaries are sometimes found quite empty, and 
sometimes so unusually narrow as to suggest a constitu- 
tional hypoplasia (270). The macrocytes tend to loitre in 
the capillaries and this has been presented as a reason why 
these patients’ complexions are as good as they are (157). 

Cardiac pain was noted as a definite feature in perni- 
cious anemia by Herrick and Nazum (267). Coombs 
(130) by special attention to this point found cardiac pain 
in eight out of thirty-six patients. In two, there was sub- 
sternal pain on exertion. One had “heavy” pain over the 
chest and shoulders. Another had a painful constriction 
around the waist. Another had a tearing, pressing pain 
in the centre of the chest and in the arms. Another com- 
plained of midsternal pain during the examination. In all 
these, pain was brought on by exertion. One had atheroma 
of the aorta, while one died from severe precordial pain. 
Reid’s (519) enquiry indicated a note-worthy absence of 
sclerotic changes in the heart. 


SYSTEMS 209 


Cardiac hypertrophy, sometimes very considerable, is 
often associated with the disease. In Cabot and Richard- 
son’s (88) series of nineteen cases, eighteen showed a 
definite hypertrophy or dilatation. In only three of these 
could possible causes for the hypertrophy be found in the 
heart itself, while in the other fifteen cases none of the 
usual causes or accompaniments of cardiac hypertrophy 
were present. Coronary sclerosis was found in but one 
case, while slight arteriosclerosis in the aortic arch and 
of the abdominal aorta were noted in several of the cases. 

Systolic murmurs, to some extent “hemic” in char- 
acter have been recognized for over fifty years as almost 
constant findings, heard at the base and in various valve 
areas. They may be heard in only a little over half the 
cases on first examination, since they may not be present 
at the moment the stethoscope is first applied. Needless to 
remark, valvular disease is not a part of pernicious anemia. 
In view of Cabot’s (87) demonstration of the rarity of 
true valvular insufficiency, such an explantion and the 
usual one had better be withheld. If murmurs are due to 
vibration of the valve cusps, then possibly the momentum 
of the blood with its reduced specific gravity does not 
furnish sufficient impact to hold the valves steady. 

The fatty change in the myocardium is conspicuous. In 
fact this is the only disease in which very marked fatty 
degeneration of the heart muscle occurs. The papillary 
muscles of the left ventricle usually present a yellow, 
striated appearance like a tiger’s skin, and in severe cases 
even wider territory may be involved. The mural muscul- 
ature never presents a normal red color and varies from 
a reddish-gray to a frankly yellow color. Microscopically, 
fat lies in scattered foci in the muscle fibres, replacing to 
some extent the contractile substance. Reid (519) takes 
the view that the infiltrated fat is brought to the heart by 
the blood in a normal physiological manner, and that the 
fatty change does not impair myocardial efficiency. This 


210 PERNICIOUS ANEMIA 


view seems to be somewhat extreme. Much discussion has 
centred on the fatty changes in the heart, liver and kidney 
as well as in the medullary substance of the nervous sys- 
tem, but it is our duty to do little more than note its 
occurrence. In patients dying with symptoms of acute 
heart failure after blood transfusions, it is not clear that 
death can be attributed to the heart alone. Possibly it 
cannot be attributed to the heart at all. 

Reid’s (519) electrocardiographic studies revealed no 
abnormalities of any significance. The Q.R.S.T. inter- 
val was of normal duration, the inference being that the 
ventricular systole is not lengthened and that the increased 
output of the heart cannot be due to such a factor. 

The increased pulse rate is due, in part at least, to the 
heart’s effort to compensate for the anemia. The pulse is 
usually regular, full and easily compressible. The systolic 
pressure disproportionately low, with a resulting high 
pulse pressure. Addison and Elliotson both noted the 
stimulation of the pulse rate and force caused by exertion 
or emotion. Some observers have noted that individuals 
were hypertensive before the disease (495). 


THE RESPIRATORY SYSTEM 


Emphysema, noted in sixty per cent of cases, may par- 
tially explain the distressing dyspnoea, and is no doubt 
due to nutritional disturbances causing atrophy of the 
elastic tissue with consquent dilatation of the air vesicles 
(605). Hydrothorax, which occasionally occurs, may be 
attributed to associated myocardial weakness. Pleural 
effusion of less extent is not very uncommon. The chronic 
hacking cough characteristically seen in the last weeks of 
life is due to pulmonary congestion and moderate edema, 
the latter caused partly by circulatory weakness and 
partly by increased filterability of the blood. Pulmonary 
edema of marked degree is a common terminal event, the 
patient drowning, while comatose, in his own secretions. 


SYSTEMS 211 


Symmer (605) suggests that the pulmonary edema may 
be due to disproportionate activity of the two ventricles, 
the left being relatively weak through fatty transform- 
ation, and cites Welch’s (639) experimental edema of 
the lungs produced by compression of the left ventricle. 
At autopsy the pleural fluid is increased in amount and 
tinged with bilirubin. Many cases show subpleural puncti- 
form hemorrhages, merely a local manifestation of the 
general condition of functional purpura. Many patients 
die of pneumonia. Tuberculosis of the lung is practically 
never seen. Mathias (408) would explain this by reduced 
oxygen tension of the tissues. 


THE GENITO-URINARY SYSTEM 


A trace of albumin is so commonly to be found in the 
urine in cases of pernicious anemia, that many have been 
temporarily diagnosed as nephritis, and the expression 
“the nephritis of pernicious anemia” has come into being, 
although into little use. 

Steiglitz (597) found evidence of mild renal damage, 
as signified by the presence of albumin or casts or both. 
On reviewing Cabot’s five hundred and six cases of whom 
forty-six per cent had albuminuria, fifty cases at the 
Johns Hopkins Hospital, of whom 62 per cent had albumi- 
nuria or casts or both, and one hundred cases at the Pres- 
byterian Hospital, Chicago, of whom fifty-seven per cent 
showed similar findings, this author finds a total of pre- 
cisely fifty per cent exhibiting evidence of renal damage. 
But in one hundred cases of secondary anemia at the last 
named hospital, only fourteen per cent showed albumin 
or casts and of these fourteen cases, four had definite 
nephritis or lesions of the urinary tract. Steiglitz there- 
fore concluded that disturbance of renal function was 
common in pernicious anemia. 

Histological examination of the kidneys revealed de- 
generation of the tubular epithelium due probably to the 


212 PERNICIOUS ANEMIA 


evident deposition of iron pigment in the convoluted 
tubules. Iron in these cells inhibited the passage of water 
and total solids and reduced the specific gravity of the 
urine. Steiglitz also found that fixation of the specific 
gravity and increase of night over day volume was char- 
acteristic. While the tendency is thus to attribute to 
hemosiderosis rather than to anemia the renal manifesta- 
tions in this disease, it must not be forgotten that all 
parenchymatous, active tissue is probably involved meta- 
bolically by the fundamental, though as yet unascertained, 
causative process. 

Christian (110) considered the kidney was affected by 
a nutritional or toxic disturbance in the renal cellular 
activity. Using renal dietary tests he found that pernicious 
anemia was accompanied by impairment of renal function 
similar to that found in patients with advanced nephritis. 
But in pernicious anemia no other evidence of chronic 
nephritis exists and the disturbance appears due to the 
anemia, decreasing with subsidence of the severity of the 
anemia unless the anemia is maintained so long that per- 
manent disturbance of renal functions ensues. 

Percy (495) has noted pernicious anemia occurring in 
individuals with chronic nephritis and hypertension, and 
has remarked on the fact that hypertension is maintained, 
even in the presence of severe anemia and adynamia, until — 
the terminal stage of the disease. 

The urine may be dark, during severe stages of the 
anemia, from the presence of urobilin. Pigment granules, 
intracellular or free, in the urine indicate siderosis of the 
kidney (540). 

Bladder symptoms—difficulty in micturition and reten- 
tion—result from disturbed innervation secondary to 
degeneration of the spinal cord. Woltman (663) found 
that of one hundred and twenty-one patients with cord 
involvement, eight per cent had partial incontinence and 
eight-tenths per cent had complete incontinence, that 


SYSTEMS 213 


retention was partial in four per cent and complete in 
eight-tenths per cent. Hamilton and Nixon found among 
forty-one patients, six with urinary incontinence on 
admission. These symptoms may improve with remissions 
and recur with relapses (580 A). “Cord bladders” ordin- 
arily occur late in the disease. In exceptional cases where 
rapid cord degeneration preceded the anemia, urinary 
incontinence has been the initial complaint for which the 
patient sought relief. In elderly men the occurrence of 
prostatic obstruction may lead to an erroneous diagnosis 
of “cord bladder.” 

Sexual vigor in the male suffers very early in cases 
where the spinal cord degenerates. 

Menstruation frequently ceases during severe anemia 
and may reappear during a remission. When it does not 
reappear it is an open question whether pernicious anemia 
has caused the menopause or whether the menopause has 
merely coincided with the disease. Certainly, the fact that 
the disease is commonest at the ages when the menopause 
most frequently occurs would rob an etiological theory 
based on the gonads of all probability of correctness. 


THE EYES 


The description by de Schweinitz (147), the first to 
appear on this subject in America, was discussed by 
Knapp and covered the subject completely. Earlier reports 
had appeared in England and on the continent (400, 513, 
547, 615). 

The ophthalmoscopic picture comprises the following 
changes: (1) pallor of the disc; (2) cloud-like edema of 
the retina, most marked in the retinal periphery; (3) 
exudates or plaques; (4) flame-shaped and irregular 
hemorrhages in the neighborhood of the papilla; (5) 
hemorrhagic areas containing a yellowish centre, or iso- 
lated yellowish-white spots which probably correspond to 
hypertrophied and degenerated nerve fibres. 


214 PERNICIOUS ANEMIA 


The microscopic histological changes include: (1) 
hemorrhages in the various strata of the retina but most 
marked in the nerve-fibre layer; (2) marked peripheral 
edema of the retina. 

There is no ground for considering these changes to 
indicate an infectious retinitis, since inflammatory signs 
are absent. 

Retinal changes showing some or all of the features 
described—especially hemorrhages—occur in from forty- 
four to sixty-two per cent of all cases at the height of the 
disease. Woltman found them in thirty-three per cent (of 
low grade) and thirty per cent (with hemorrhages) in a 
series of one hundred and fifty cases. These retinal hem- 
orrhages are indicative of the functional purpura exist- 
ing, and since they may be found in severe anemias of 
known etiology (for example, that of D. latus infection, 
121) and in chlorosis, they are not of great diagnostic 
value. 

Goss (233) has shown that blood transfusions produce 
no immediate effect on the retinal changes, do not prevent 
further occurrence of hemorrhages, and do not cause the 
hemorrhages to be any more rapidly absorbed, although a 
remote effect of transfusion is a gradual lessening of 
retinal edema, and a decreased tendency to hemorrhages. 


THE EAR 


While it is now well recognized that noises in the ears 
occur with great frequency not only in pernicious anemia 
but other anemias as well, and that in pernicious anemia 
they seem related quite definitely to changes in the blood 
volume, the report of Schwabach (566), which reviewed 
the literature, indicates that deafness may occur from 
hemorrhages interfering with either the sound-conducting 
or sound-perceiving apparatus. 


CHAPTER X 
DIAGNOSIS AND PROGNOSIS 


While it is a truism to state that the more intimate one’s 
knowledge of pernicious anemia becomes, the fewer will 
be the diagnostic difficulties encountered, the statement 
may nevertheless be pardoned in view of the many fea- 
tures presented by this disease. 

Early diagnosis is becoming increasingly desirable in 
view of the recently demonstrated success of the liver- 
diet in treatment, and it is precisely in early cases, before 
the blood picture has become fully developed, that most 
of the perplexity arises. 

Again, so many systems are involved, that great oppor- 
tunity exists for suggestions of other disease to creep in, 
particularly in view of the fact that certain other anemias 
have somewhat similar blood pictures. 


EARLY DIAGNOSIS 


We are beginning to recognize a fairly well-defined 
condition which precedes this disease and which, in its 
several variations, might be referred to as “pre-pernicious 
anemia.” 

The chief characteristic of this condition is achlor- 
hydria—the one obligatory feature. Achlorhydria alone 
does not constitute the condition but only when it is asso- 
ciated with one or more of the following features—spinal 
cord involvement, glossitis, and the earliest blood changes. 

These early blood changes are to be understood as those 
which appear before any actual oligocythemia is present 
and consist of the following: increased volume index 
and anisocytosis. 

A patient complaining of glossitis, or of numbness and 
tingling in the extremities, or both, may be regarded— 
provided he has achlorhydria—as a potential case of 


[ 215 ] 


216 PERNICIOUS ANEMIA 


pernicious anemia, even if his blood showns no change 
whatever. The suspicion is rendered certain if he has, 
additionally, an increased volume index or anisocytosis, 
or both. 

The least positive evidence which could place a patient 
in this early suspected group is a combination of achlor- 
hydria and increased volume index. 

There is also an apprehensive neurosis very commonly 
met with in this pre-pernicious anemia state, which ap- 
pears to be a specific early involvement of the psychic 
function and may be regarded as part of the disease. It 
may occur in patients whose mental histories, personal 
and family, are negative. 

Early diagnosis is facilitated by bearing in mind the 
fact that pernicious anemia is not a disease of the blood 
alone but affects also the digestive and nervous system 
(439). It is quite justifiable to diagnose the disease in the 
absence of anemia, when other systems present incrimi- 
nating evidence. 

The specific anemia with disturbed corpuscular mor- 
phology and high color index, characteristic of the full- 
established blood picture may, in some cases, supervene 
rather suddenly upon a blood condition seemingly normal. 
In other words, disturbed morphology is obvious as soon 
as any anemia occurs and we may say that the specific 
anemia appeared “out of a blue sky.” 

In other cases, the patient has had a simple anemia with 
low color index for some time previously. This has been 
due, in some instances, to focal infection, to intestinal 
indigestion, or other rather obvious causes. It has been 
due, in some cases, apparently to achlorhydria, for it has 
been well demonstrated that achlorhydria itself is accom- 
panied, more often than not, by a simple fluctuating 
anemia with red corpuscles usually smaller than normal 
(56, 187). All patients in these simple anemia groups 
may develop pernicious anemia, in which case the specific 


DIAGNOSIS AND PROGNOSIS 217 


morphological features are merely superadded to an al- 
ready existing simple anemia. 

A physician ought to be particularly suspicious of a 
simple anemia occurring in connection with achlorhydria, 
and to look for glossitis and disturbances of sensation 
even though the smear picture indicates no morphological 
abnormality. 

The earliest appearance of anisocytosis will usually be 
accompanied by reduction in the hemoglobin percentage, 
even though the red blood cells are not as yet reduced in 
number. 

In the early stages of the anemia a color index less 
than one per cent ought not to forbid the diagnosis pro- 
vided this is the only consideration against it. 

Furthermore, leukopenia and reduction of the blood 
platelets may not be striking in early cases, because these 
features indicate a more intense marrow involvement 
than usually occurs at first. The power of the marrow to 
sustain even a mild leukocytosis, in the presence of infec- 
tion, is particularly to be remembered in early cases, for 
the diagnosis is justifiable where, in an early case, a white 
blood count of thirteen thousand per cubic millimeter 
is found as a result of some recognizable infectious 
complication. 

Inasmuch as patients with achlorhydria are somewhat 
prone to infections such as cholecystitis, pyorrhoea alveo- 
laris, apical abscess, and appendicitis, and inasmuch as 
achlorhydria is always associated with gastritis and may 
be associated with exophthalmic goitre (450) and with 
arthritis deformans, it follows that every anemia occur- 
ring in connection with any of these conditions should be 
intensively studied from the standpoint of tongue changes, 
cord changes, and morphological blood changes. Such a 
study will be rewarded quite frequently by an early diag- 
nosis of pernicious anemia. 


218 PERNICIOUS ANEMIA 


Certain of the constitutional peculiarities of the patient 
should be kept in mind, especially prematurely gray hair, 
and the feminine bodily characteristics of the male pa- 
tients previously referred to. 

There is no doubt that if all the facts of pernicious ane- 
mia are kept constantly in mind, the early detection of 
characteristic symptoms, and of pathognomonic symp- 
tom-groups, will become a much more common accom- 
plishment. 


DIAGNOSIS AFTER THE ANEMIA IS ESTABLISHED 


Real difficulty is occasionally encountered in differenti- 
ating this disease from the following diseases in particu- 
lar—cancer of the stomach, syphilis, sprue, the chronic 
hemolytic anemia of pregnancy and dibothriocephalus 
anemia. These various conditions will be briefly described 
with emphasis on the points of difference from perni- 
cious anemia. 

Cancer of the stomach (67, 255, 256, 348, 527, 585, 
644). In all cases of cancer of the stomach the gastric 
acidity is reduced, while achlorhydria occurs in fully 50 
per cent, as judged by the fractional test meal. Therefore 
in half the cases, the one fundamental physiological fea- 
ture of pernicious anemia is present. It is unusual for gas- 
tric carcinoma not to be accompanied by anemia of some 
type and of some grade, at some stage. In by far the great 
majority of cases this anemia is of a simple type—low 
color index and regular cellular morphology. This simple 
anemia may, however, be very severe. There are three or 
four possible factors which may be considered as causing 
this simple anemia—disturbance of nutrition consequent 
upon anorexia, obstruction and fermentation, septic in- 
fection in and around the cancerous area; loss of blood 
by hemorrhage or constant oozing from the ulcerated 
growth or from a polypoid growth, and, finally, a factor 
upon which sufficient emphasis has perhaps not been 


DIAGNOSIS AND PROGNOSIS fag) 


placed, viz., the absorption into the blood of hemotoxic 
autolytic products of the cancer itself. However it may 
be caused, this simple anemia of varying severity is usu- 
ally the type present and the type which remains until 
death. 

There is a second type, more severe, which occurs in a 
lesser number of cases, characterized by features common 
to both simple and pernicious anemia. The color index is 
low, achromia is prominent; but, on the other hand, ma- 
crocytosis is present. The macrocytes, however, are defi- 
nitely circular in outline and show achromia, whereas in 
pernicious anemia the macrocytes are nearly all oval in 
outline and never show, during active phases, any achro- 
mia of importance. 

Finally, there is the third type, the cases being few in 
number, which resembles Addisonian anemia sometimes 
very closely—high color index and oval macrocytosis. 
Even in these cases, there does not occur so much reduc- 
tion in the leukocytes, and this is a ready point in differ- 
entiation. The remarks that apply to this form of anemia 
apply equally to the “pernicious-like”’ anemia which occa- 
sionally accompanies carcinoma of the colon. In both, 
besides this macrocytic anemia, glossitis sometimes occurs 
and makes distinction from pernicious anemia very diffi- 
cult. But the lack of myeloid depression, as evidenced by 
lack of leukopenia, is a point to be repeated and empha- 
sized. Another diagnostic point of importance is a low 
icterus index. So far as critically reported, the degree of 
bilirubinemia in these severe anemias of gastric cancer 
is within normal range, whereas in pernicious anemia it 
is considerably increased in the vast majority of cases. 
This difference in the bile pigment distribution, if it con- 
tinues to be reported, should do much to differentiate this 
“cancer anemia.” 

When metastases form in the bone marrow a similar 
pernicious-like anemia develops, although here again 


220 PERNICIOUS ANEMIA 


marked leukopenia seldom occurs. During life, pain over 
the bones involved may suggest this condition. At autop- 
sy cases of this severe anemia of gastric carcinoma fail 
to show characteristic hemosiderosis of the liver. 

Cancer of the stomach not infrequently complicates an 
already existing pernicious anemia. The presence of true 
Addisonian anemia is indicated by spinal cord involve- 
ment and increased icterus index, neither of which are 
likely to be present with gastric cancer. 

Marked loss of weight may occur in pernicious anemia 
and is therefore an unreliable criterion in diagnosis. 

If the presence of a gastric cancer has been proved, 
then the problem of whether the anemia is due to this 
cancer or due to associated pernicious anemia is often one 
to tax the resources of the clinician. In some cases a 
double diagnosis is quite justifiable. 

Syphilis (208, 271, 512, 592). The statement is occa- 
sionally seen in the literature that the blood of patients 
with pernicious anemia often gives a positive Wasser- 
man reaction in the absence of syphilis. The writer recent- 
ly did blood Wasserman tests on sixty-four consecutive 
patients with true pernicious anemia. The cases were all 
derived from the rural parts of Ontario where syphilis is 
uncommon. The tests were carried out first by the modi- 
fication of the original Wasserman as employed at the 
Johns Hopkins Hospital, using their antigen, and checked 
by the Kolmer Wasserman method at the Ontario Public 
Health Laboratories, Toronto, through the co-operation 
of Anderson. The results were consistently negative by 
both methods. The patients from whom these blood sam- 
ples were taken were in various stages of the disease from 
perfect remissions to coma. The reactions were carried 
out within twenty-four hours of the time of taking the 
samples. We are persuaded that a positive Wasserman is 
uncommon in uncomplicated Addisonian anemia. 


DIAGNOSIS AND PROGNOSIS 221 


This means, we believe, that when a positive Wasser- 
man is obtained on a fresh sample of pernicious anemia 
blood, the question of syphilis should be seriously con- 
sidered. 

Cases of severe macrocytic anemia very strongly sug- 
gestive of pernicious anemia may be encountered in indi- 
viduals with tertiary syphilis, especially during the late 
period of the disease when cachexia is evident. If the 
anemia can be entirely and permanently cured by anti- 
syphlitic treatment, it is fair to believe that it was due to 
syphilis, since such treatment cannot cure pernicious 
anemia. 

Clinical distinction must rest on finely drawn micro- 
scopic evidence—the shape of the macrocytes, the degree 
of myeloid depression—on the icterus index and associat- 
ed signs in the tongue and nervous system. 

Post mortem it may be possible to judge from the bone- 
marrow reaction and liver siderosis which disease caused 
the anemia. 

In urban centres where syphilis is common, the two dis- 
eases may co-exist, and, where justifiable, the double 
diagnosis should be made. 

These cases with syphilis do cause great perplexity and 
it must be admitted that syphilis of itself can cause a very 
severe macrocytic, pernicious-like anemia, and even, at 
times, characteristic cord changes. 

The etiological dilemma thus arising has already been 
sufficiently discussed. 

Sprue (1, 66, 169, 207, 465, 471, 517, 622, 661). The 
anemia of sprue resembles that of pernicious anemia, al- 
though in the great majority of cases the Price-Jones 
graph in sprue shows less shifting of the curve to the 
right. It is nevertheless true that the smear picture bears 
a striking resemblance to that of pernicious anemia. 
Marked oligocythemia, high color index, and a delayed 
Van den Bergh reaction are other points of resemblance. 


222 PERNICIOUS ANEMIA 


Finally, the common occurrence of glossitis in sprue adds 
a feature which renders confusion with pernicious anemia 
inevitable. 

In a large proportion of sprue cases, however, the dif- 
ferentiation can be made by several points. The gastric 
contents contain free HCl, the degree of anisocytosis is 
not so great, and the diarrhoea tends to be of a fermen- 
tative type and to occur chiefly in the morning. Cord symp- 
toms are usually absent and the dorsum of the tongue 
shows central rather than peripheral fissuring, and 
atrophy of filiform papillae near the tip rather than gen- 
eral papillary destruction. 

Where achlorhydria appears it can often be followed 
in its development during the disease, and it is therefore 
not a pre-existing condition as it is thought to be in per- 
nicious anemia. 

But difficulty of a very perplexing nature arises in 
some cases, for sprue sometimes presents so faithful a 
picture of pernicious anemia, even to the gastric, tongue, 
and cord symptoms, that differentiation is practically im- 
possible and either diagnosis may be made with equal 
justification. Wood has brought this dilemma very forci- 
bly to the attention of the profession. He has sent the 
writer smears from such cases which would certainly be 
accepted as smears from pernicious anemia. He found the 
monilia psilosis in the stools, tongue, or gums of all these 
difficult cases, as well as in frank cases of sprue, but not 
in cases who had neither sprue nor pernicious anemia. 
Complement fixation reactions on the blood, using anti- 
gens prepared from the M. psilosis were found to be use- 
less for diagnostic purposes, since positive reactions may 
occur in any individual who harbors the monilia, whether 
the individual is well, has sprue or has pernicious anemia. 

While most cases of sprue can easily be differentiated 
from pernicious anemia, a few cases present so close a re- 
semblance that either diagnosis is permissable. Pernicious 


DIAGNOSIS AND PROGNOSIS 2S 


anemia has hertofore been almost invariably fatal while 
sprue has by no means been invariably fatal. 

The chronic hemolytic anemia of pregnancy (38, 118, 
154, 174, 175, 200, 201, 216, 228, 250, 261, 329, 443, 478, 
541, 548, 558, 565, 577, 626). No perfectly satisfactory 
classification or systematic description of the anemias oc- 
curring in pregnancy has been made. But it is recognized 
that a simple anemia is likely to occur in the early months 
of gestation and improve toward term; it is also evident 
that simple anemia may result from uterine hemorrhage, 
either sudden and extensive, or prolonged and moderate; 
also there‘is no doubt that puerperal sepsis may cause a 
severe simple anemia. None of these forms should be mis- 
taken for another and rarer form, the so-called “perni- 
cious anemia of pregnancy’’, or better, “the chronic hemo- 
lytic anemia of pregnancy.” For some reason the obstetri- 
cians do not seem as familiar with this form as the inter- 
nists, probably because this anemia usually comes on near 
or after term and patients are transferred to the medical 
wards of hospitals. In Maryland, Williams has seen only 
two cases, while among the hospitals of Ontario the dis- 
ease is not very uncommon. It might be briefly described 
as pernicious anemia associated with pregnancy, but 
this description is fallacious since differences exist. 
The chief differences are as follows: absence of glossitis 
and cord changes, an average red blood cell diameter of 
less than normal in spite of the presence of macrocytes, 
the presence of marked achromia, higher reticulated cell 
counts, and increased fragility of red corpuscles to hypo- 
tonic salt solutions. Minot regards this disease as a variety 
of chronic hemolytic jaundice. Its cause is pregnancy, and 
when pregnancy is past, many patients permanently re- 
cover. So far as critically reported, achlorhydria has been 
present, although reports on this point are few. Usually 
there is not so great a degree of leukopenia as in perni- 
cious anemia and the blood platelets may be normal in 


224 PERNICIOUS ANEMIA 


number. At other times there is evident marrow depres- 
sion and retinal hemorrhages are present. As a working 
principle, one is justified in placing a patient in this group 
when the blood findings are somewhat atypical and when 
tongue and cord symptoms are absent. A point of distinc- 
tion is the fact that these cases may recover permanently. 

Dibothriocephalus latus anemia (36, 121, 193, 405, 
546, 552, 551, 606, 607). While the writer is not familiar 
with this form of anemia in practice, it appears from the 
continental literature and from sporadic reports in Ameri- 
ca that very occasionally the fish-tapeworm infection is 
capable of producing an anemia indistinguishable from 
that of pernicious anemia. The incidence of glossitis, 
achlorhydria and cord change is not exactly reported. 
The stools should be examined for the ova or the worm 
itself, especially in worm-infested populations, and where 
these are found the diagnosis of bothriocephalus anemia 
is justified. If the worm is expelled sufficiently early, com- 
plete recovery takes place. 

While the above mentioned five diseases present the in- 
stances where differential diagnosis is very difficult, and 
sometimes impossible, there are still other diseases which 
may be confused with pernicious anemia for various 
reasons. 

Anemia from acute or chronic sepsis may at times pro- 
duce a somewhat similar blood picture, especially infec- 
tions with hemolytic streptococci and the malaria plasmo- 
dium. Differentiation rests on the finding of a sufficient 
cause, on strict microscopic evidence in the blood, and the 
absence of associated signs in the tongue and spinal cord. 
In these cases, marked bone-marrow regeneration may 
cause a flooding of the circulation with immature white 
blood cells, a condition which has been unhappily called 
leukanemia. 

Chemical poisoning with anilin derivatives, and nitro- 
and benzol products may be confusing, but the clinical pic- 


DIAGNOSIS AND PROGNOSIS 225 


ture is not that of pernicious anemia. Hemolytic anemia 
is often seen following the intensive treatment of syphilis 
with benzol derivatives. 

Aplastic anemias, both idiopathic and those produced 
by radium and mesothorium (209, 395, 520, 643) or by 
osteosclerosis, may usually be differentiated by the smear 
picture, and almost always by the low icterus index and 
absence of the cardinal clinical signs of pernicious anemia. 

In the aleukemic phase of leukemia, a blood picture 
like that of pernicious anemia may occur, but should not 
present great difficulty when reference is made to other 
features (76). Secondary cancer metastases to the bone 
marrow may also produce a blood likeness. Some cases of 
polycythemia, in the terminal stages, may resemble the 
pernicious anemia blood picture, but should be readily 
differentiated (113). 

The symptom—purpura—may confuse, since it is com- 
mon to severe aplastic anemia, purpura hemorrhagica, 
and the bone-marrow exhaustion stage of pernicious ane- 
mia, and because, especially, any marrow involvement 
sufficient to cause thrombocytopenia may produce a ma- 
crocytic anemia. Associated signs must be here kept in 
mind. 

Endocarditis, especially when due to hemolytic strep- 
tococci, may confuse because of cardiac murmurs, en- 
larged spleen, fever, and toxic involvement of the mar- 
row. The history of the case, blood cultures, careful evalu- 
ation of the blood picture and the degree of illness of the 
patient will usually help to decide the diagnosis. 

Addisons’ disease, nephritis and nephrosis, and arteri- 
osclerosis may present superficial resemblance. 

Tabes dorsalis or multiple sclerosis may be incorrectly 
entertained because of the subacute combined degenera- 
tion of the spinal cord. 

Chronic hemolytic jaundice may confuse because of 
the icterus but the blood picture is different in the ma- 
jority of cases. Macrocytosis is less and the macrocytes 


226 PERNICIOUS ANEMIA 


are circular rather than oval, the icterus index is higher, 
there is not so great a degree of bone-marrow depression 
as indicated by the presence of more leukocytes and blood 
platelets, while immature forms, especially reticulocytes, 
are more plentiful. The gastric secretion is usually nor- 
mal. Exceptional cases, however, in which the marrow is 
greatly involved may present a striking likeness to the 
middle type of pernicious anemia, in which rapid regener- 
ation is a continuous feature. 

Splenomegaly, a feature of many diseases, is rather an 
uncommon feature of pernicious anemia, but it does oc- 
cur. Chronic hemolytic jaundice, Banti’s disease (the 
identity of which seems uncertain), Gaucher’s disease, 
the enlarged spleen of syphilis, chronic sepsis, tubercu- 
losis and malaria, idiopathic splenic anemias, and the en- 
larged spleen of polycythemia and of splenomyelogenous 
leukemia, may all at times cause trouble, but should not 
present great difficulty if the cases are thoroughly studied 
with special reference to the gastric secretion, tongue 
changes, cord changes, and minute blood changes, and 
if it be borne in mind that enlargement of the spleen— 
sometimes to great dimensions—occurs in an occasional 
case of pernicious anemia. 

The abdominal crises sometimes seen in pernicious ane- 
mia, as a result of spinal cord disease, as well as the 
epigastric pain which is sometimes a part of the disease, 
may frequently lead to a diagnosis of an acute abdominal 
pain, but this mistake can usually be avoided by a thor- 
ough study of the case from every angle. 

Myxedema may very occasionally give rise to a con- 
fusing blood picture and might be very difficult to recog- 
nize as such unless a complete critical study.of the blood 
of the gastric secretion, and the basal metabolic rate 
were made (443). 

Prognosis (54, 72, 86, 213, 391, 584, 671). Heretofore 
the average length of life from the first symptoms was a 
little over two years, in treated and untreated cases. The 


DIAGNOSIS AND PROGNOSIS 227 


liver diet has already brightened the prognosis as to 
length of life, but it would be premature to form a judg- 
ment. 

It may be said that the prognosis as to length of life 
is better in cases from which all possible sepsis has been 
eradicated and in patients without spinal cord symptoms. 
As has been stated before, remissions of five years dura- 
tion are not as uncommon as once thought. Spontaneous 
cure is not proved, but in a very few cases normal life ex- 
pectancy has been realized. 

Prognosis with regard to the likelihood of a spontane- 
ous remission can only be judged by signs indicating ces- 
sation of disease activity (fall of the icterus index and 
fever), and by signs indicating bone marrow stimulation 
(polychromatophilia, nucleated red blood cells in moder- 
ate numbers accompanied by an increased percentage of 
reticulated forms, increase in polymorphonuclear leuko- 
cytes and blood platelets). 

Prognosis with regard to the nearness of a relapse 
can only be judged by signs indicating increased disease 
activity, and by signs indicating a deepening of the bone- 
marrow involvement—lack of regenerative forms, in- 
creased disturbance of cellular morphology, decrease in 
polymorphonuclear leukocytes and blood platelets. 

Grave signs with regard to life are marked blast 
crises without considerable reticulated cell increase, ex- 
treme leukopenia and platelet reduction, and rapid exten- 
sion of the spinal cord involvement with loss of control of 
sphincters. 

Extremely grave signs with regard to life are the 
presence of macropolycytes in the circulation, the pres- 
ence in the blood of the ether soluble pigment described 
by Broun et al., and the appearance of coma. 

It would appear from the report of Minot and Mur- 
phy (447) that with the use of liver diet prognosis for a 
remission was 100 per cent good, if the treatment is prop- 
erly taken. 


CHAPTER XI 
PROPHYLAXIS AND TREATMENT 


It seems a self-evident proposition that if all cases of 
achlorhydria were placed upon the best treatment known 
for pernicious anemia that fewer (and perhaps very 
few) of the individuals would progress to the disease. 
Leake (358) has already emphasized this point. It is to 
be hoped and expected that in the near future a frac- 
tional test meal will become almost as routine in exami- 
nation as the estimation of the blood pressure. This simple 
procedure followed by cautious periodical scrutiny of 
achlorhydric individuals will constitute a prophylactic 
duty of the physician, which, through the use of the liver 
diet in very early cases, may conceivably bring about a 
considerable prolongation of the period of life expectancy. 

The various methods of treatment which have been 
given extensive trial in pernicious anemia form an im- 
posing list. Among drugs may be mentioned iron, colloidal 
iron, arsenic, benzol combinations of arsenic, phosphorus, 
quinine, calomel, perchloride of mercury, mercurochrome, 
germanium dioxide, antimony, thorium, iodin, salol and 
other intestinal antiseptics such as dimol and gentian 
violet. Among organic and biological products may be 
noted human blood, antistreptococcus serum, B. welchii 
antitoxin, streptococcus vaccines, B. coli vaccines, choles- 
terol, hydrochloric acid, thyroid, marrow, spleen, liver, 
and parenteral protein injections. Surgery has been used 
for the eradication of foci of infection everywhere in the 
body, for iliostomy, splenectomy, ligation of the splenic 
artery (630), removal of bone-marrow (33,57), resection 
of the proximal colon, and heterogenous suprarenal trans- 
plantation (591). Other procedures are lavage, enemata, 
bile drainage (227), the withdrawal of small amounts of 
blood (490), heliotherapy, ultra-violet light therapy, hy- 


[ 228 ] 


ERO PEOEAxXIS AND TREAT MEN? | 229 


drotherapy, and the use of X-Rays and radium. Diets of 
various descriptions, cultures of aciduric bacteria, butter- 
milk, kefir, alone or in many different combinations with 
other forms of treatment, have been employed. 

Arsenic was employed first by Bramwell (62,64) in the 
form of Fowler’s solution in gradually increasing doses 
on a case in the Newcastle-on-Tyne infirmary in 1877. 
Bramwell apparently used the drug empirically and ob- 
tained a strikingly good remission. Not without reason he 
later strongly recommended this form of treatment. It 
was immediately taken up by those members of the pro- 
fession who were familiar with the disease, and yet, dur- 
ing the next fifteen years, many physicians had encoun- 
tered numerous cases in which arsenic produced no appar- 
ent benefit. The theories of its action (49,599) are sev- 
eral—hemopoietic stimulant, anti-hemolytic agent, anti- 
septic agent directed especially against protozoa and 
streptococci (544,328) and, finally, a drug which has a 
“preservative” action on the red corpuscles (242,243). 
McPhedran’s (423) patient with an eighteen year remis- 
sion was kept constantly on 45 minims of Fowler’s solu- 
tion per day, but others have died taking similar doses. 
No one knows why arsenic benefits some cases any more 
than why it fails to benefit others. The use of sodium ca- 
codylate has attained considerable vogue, and so also 
has the use of antisyphilitic arsenical preparations. The 
use of benzol derivations cannot be recommended in view 
of the acute hemolytic anemia which occasionally follows 
their use (653). Fowler’s solution in gradually increas- 
ing doses by the mouth is the method of choice for it has 
never been shown that better results were obtained by any 
other preparation or method of administration, (344, 
635). The use of “shock” doses of arsenic seems unjusti- 
fiable (108). Arsenic had better never be given than given 
to the point of gastro-intestinal intolerance or to the point 
of causing peripheral neuritis or melanodermia (455). 


230 PERNICIOUS ANEMIA 


Strictly there is no reason to explain the perennial popu- 
larity of arsenic (403), yet it seems fairly certain that the 
drug will continue to be used in some form or in combi- 
nation with other methods of treatment. 

Iron was the first drug, in fact, the first form of treat- 
ment, used in pernicious anemia (171). This was sug- 
gested by the benefits of iron in chlorosis. Clinical ex- 
perience immediately branded inorganic iron as useless. 
Ferrous salts have recently been considered as even harm- 
ful (464, 579). The question of food iron will be presently 
considered. No encouraging results have followed the use 
of colloidal iron (15, 18, 639). 

Neither phosphorus nor quinine have any apparent 
beneficial effect. 

Germanium dioxide was found to exert no more bene- 
ficial effect than arsenic, though it was more easily toler- 
ated (251,461). | 

Preparations of mercury have ardent supporters. Fer- 
rier’s (198) case of long remission on calomel (and this 
patient is still living and well) is interesting, but one case 
proves nothing. Nor is there any convincing evidence that 
intestinal antiseptics such as salol or dimol exert any cur- 
ative effect. McLaughlin (418,419) does not consider in- 
travenous injections of mercurochrome a cure, but notes 
that remissions can be produced rather readily by this 
method. Fist (203) considers mercurochrome of doubt- 
ful value and thinks it may exert an effect analagous to 
that of the parenteral injections of foreign protein. 

Thorium X (206), antimony (118), and iodin (272) 
have given no evidence of benefit. The administration of 
gentian violet is of doubtful value since the report of its 
use indicates that other (dietary) methods were used 
which in themselves may have been responsible for the 
improvement (129). 

Among organic and biological products, it may be con- 
fidently stated that antistreptococcus serum (55, 632), B. 


PROPHYEA IS AND TREATMENT + 231 


Welchii antitoxin (132), vaccines made from streptococci 
and B. coli (631), exert no beneficial influence and pro- 
duce at most a foregn protein effect. 

Parenteral protein therapy with milk (284), caseosan 
(260), or other agents will frequently bring on a remis- 
sion (514), and an interesting feature of this treatment 
is a not infrequent improvement in the patient’s subjec- 
tive sensory symptoms. A very similar effect was obtained 
by the writer (132) by the use of whey cultures of B. 
acidophilus. Usually these patients experienced a decided 
lessening of the numbness in the extremities within a 
week from the time of beginning treatment. Gram has 
compared the effect of kefir feeding to that of foreign 
protein therapy. Hurst noted aggravation of parasthesiae 
after each dose of autogenous streptococcus vaccines. 
None of these methods are curative. 

Organotherapy by the use of bone-marrow (210, 285) 
and spleen has received considerable trial, first by Fraser 
with bone-marrow, and recently the dried products of 
both have been investigated by Leake and others (362, 
363, 356, 357, 360, 359, 361), not without beneficial ef- 
fect. Thyroid medication in the form of thyroid residue 
tablets has not proved encouraging although large doses 
could be given by MacBride (389) without intoxication. 
Organotherapy with whole calf’s or beef liver will be 
considered in connection with dietary treatment. It is 
doubtful if cholesterol in the diet or by subcutaneous ad- 
ministration in olive oil solution has any curative effect 
although it has been used because of its general antihe- 
molytic properties (176). 

The administration of dilute hydrochloric acid as a 
form of replacement therapy, while not constituting a 
cure, unquestionably is of benefit, especially in helping to 
control gastric symptoms and diarrhoea, and may be re- 
garded as a perfectly rational form of treatment to be 
recommended in connection with any other form of treat- 


232 PERNICIOUS ANEMIA 


ment (501, 574, 152). From 1 to 2 drams of the dilute 
acid, in water, orange juice, or milk should be taken in 
sips during meals. Hurst gives, in addition to this, animal 
charcoal for its adsorptive effects in the control of flatu- 
lence. 

Blood transfusion may be regarded as a form of 
organotherapy. As a method of treating pernicious 
anemia it was employed quite early in the history of the 
disease (589, 104), and has been in continual extensive 
use for the past twenty years, having been made more 
feasible by modern methods of blood matching. Several 
references have been made already to the metabolic effects 
of blood transfusion. It is not proposed to consider here 
the extensive literature of the subject. The final judgment 
of blood transfusion in pernicious anemia is that it does 
not cure the disease, does not prolong life, may or may 
not induce a remission, but that it will always reserve for 
itself a place in treatment since it can be employed at 
times of emergency when a patient is too ill to receive any 
other form of treatment now available. Methods of blood 
typing, blood matching, and of transfusion, as well as 
descriptions of reactions to transfusion (58) may readily 
be obtained from many sources (441). 

The eradication of foci of infection, is, on general 
principles, just as rational a procedure in pernicious 
anemia as in any other disease. It is perhaps even more 
urgent than in some diseases owing to the fact that sepsis 
of itself may be responsible not only for a considerable 
proportion of the symptoms, particularly the gastric 
symptoms, but also for some degree of the anemia. Hun- 
ter (305) has well indicated that the eradication of infec- 
tion where possible somewhat ameliorates and lengthens 
the course of the disease. In all cases, however, the 
strength of the patient must be carefully balanced against 
the benefits to be derived from the treatment, and where 
the latter consists in opening the abdomen, due dis- 


PROPHYLAXIS AND TREATMENT) 233 


cretion should be used. It seems questionable whether 
abdominal surgery, except for emergency purposes, is 
permissable in pernicious anemia (263). As a practical 
point, diseased teeth ought not to be removed at one sit- 
ting but at several sittings at sufficient interval to allow 
the patient to recover from shock, and particularly to pre- 
vent the gum tissues from being suddenly subjected to an 
extensive infection. 

Ileostomy (84), for some unknown reason, almost 
invariably produces improvement so long as the bowel 
remains open. Resection of the proximal half of the colon 
has not been found to be a justifiable procedure (412). 
Excochleation of bone-marrow from the long bones has 
been tried and is certainly to be strongly condemned in 
view of the results (633, 617). 

Splenectomy in pernicious anemia was advised by 
Eppinger (173) upon the theory that the spleen played a 
primary etiological role in the disease. Various effects of 
splenectomy on the metabolism and blood picture have 
already been mentioned. The operation does not cure the 
disease and seldom prolongs life. Splenectomy, however, 
is usually followed by a remission, and by improvement 
in the bile-pigment condition. The limited group of cases 
which show splenic enlargement are the only one upon 
which this operation is justifiable. Cases with splenome- 
galy, high icterus index, marked increase of bile pigments 
in the duodenal contents, and showing an acute course, 
are frequently very decidedly benefited by the operation, 
but splenectomy must be done in as early a stage of the 
disease as possible, before cachexia has begun to appear 
and even before any marked degree of marrow exhaustion 
is in evidence. Life is prolonged by splenectomy in such 
cases, and the operation should be reserved only for such 
cases. 

The use of ultra-violet rays (613), X-Rays, and radium 
are all very disappointing in themselves (239), but it is 


234 PERNICIOUS ANEMIA 


possible that the use of the mercury vapor lamp may be 
of assistance in association with other forms of treatment. 

The diets which have been recommended for pernicious 
anemia have been devised upon various observations of 
the symptoms and findings. Fenwick (199) recommended 
a diet relatively rich in protein and sparing in farinaceous 
foods. Hunter (296) advised the use of farinaceous foods 
in preference to proteins, with the idea of lessening intes- 
tinal putrefaction. Others have advised various kinds of 
diets with several empirical ideas in mind. Foods contain- 
ing iron in largest quantities, especially vegetables, have 
been recommended and commonly used, in spite of the fact 
that most physicians knew that inorganic iron was prac- 
tically useless. The treatment of the disease by Barker 
and Sprunt (25), in which over-feeding was practised as 
a part of the treatment, caused more interest to be taken 
in the subject of diet as a means of treatment. Mosenthal 
(454) and later Peppard (491) found that by overfeeding 
they could readily obtain positive nitrogen balances in 
pernicious anemia. 

The important experimental work of Whipple, Rob- 
scheit-Robbins (648, 651, 652), and their associates on 
the effect of various kinds of foods on blood regeneration, 
begun in 1920 and still being pursued, has exerted a pro- 
found effect, indirectly, upon the treatment of clinical 
anemias. They found that dogs, rendered anemic by 
hemorrhage, regenerated their blood much more rapidly 
when fed certain kinds of food, particularly liver. The 
high amount of food-iron contained in liver was consid- 
ered the chief reason for its beneficial influence. 

In 1921 Fenlon (195) recommended for pernicious 
anemia a diet high in animal liver because of the con- 
tained nucleoprotein. 

Gibson and Howard (223) were the first, judging from 
the literature, to apply the experimental findings of 
Whipple et al. to the treatment of pernicious anemia, in 


PROPHYLAXIS AND TREATMENT 235 


an attempt “‘to test the efficiency of Whipple’s high iron 
diet when given to patients suffering from idiopathic 
anemia.” The diets they used contained “fruits, green 
vegetables, lima beans, sweet potatoes, egg yolk and liver 
(daily), the constituents being selected to provide a ration 
rich in iron and relatively low in fat.” The caloric and 
protein values were also relatively low. The beneficial 
effects of this diet have already been referred to in Chap- 
ter VII in connection with the metabolism of nitrogen 
and iron. It is to be noted particularly that liver formed 
a constant daily part of this diet, and that metabolic and 
clinical as well as hematological improvements were noted 
as constant results in a series of very carefully controlled 
experiments on eleven patients with this disease. Gibson 
and Howard felt that, while due allowance was to be made 
for spontaneous remissions occurring, this high food-iron 
diet was to be strongly recommended in treatment. 

The special diet used by Minot and Murphy (447) was 
devised as a result of many observations. The main ele- 
ment was food rich in food-iron and complete proteins, 
particularly liver. In addition to this, the fat and carbo- 
hydrate were reduced, and vitamine containing fruits 
and vegetables added. They had previously tried out clin- 
ically the high food-iron diet found by Whipple et al. to be 
beneficial in blood regeneration after experimental anemia 
from hemorrhage, and had concluded that this diet was of 
clinical value. Fat was reduced because of the hemolytic 
effect of unsaturated fatty acids, because lipoids are 
growth-inhibiting, and because many patients with per- 
nicious anemia gave a history of having eaten an abnor- 
mal proportion of fat in their routine diets over years. 
Gibson and Howard (223) previously noted a less favor- 
able iron balance in two of four patients who received a 
larger ration of fat than the others, and advised that a 
further study of fat ingestion in pernicious anemia should 
be carried out. 


236 PERNICIOUS ANEMIA 


Minot and Murphy tried their diet on forty-five pa- 
tients with the result that all their patients showed a 
prompt, rapid and distinct remission of their anemia. 
This, incidentally, is the first and only instance in the his- 
tory of the disease, in which any form of treatment has 
produced invariable remission in so large a series of pa- 
tients. The average red blood cell counts for the whole 
group rose from 1,470,000 per cubic millimeter before 
starting the treatment to 3,400,000 at the end of the first 
month ; and for twenty-seven cases observed from four to 
six months after the diet was begun the average had risen 
to 4,500,000. The first signs of blood improvement were 
early decrease of the icterus index and early temporary 
increase of the reticulocytes. Constipated patients and 
patients with diarrhoea soon came to have normal bowel 
movements. Marked clinical improvement accompanied 
the blood improvement. None of the patients who re- 
mained on the diet had relapses, although two years had 
elapsed in a few of the cases since beginning the treat- 
ment. They noted no improvement in marked objective 
spinal-cord changes. The following instructions, issued by 
these investigators, give a concise and practical conception 
of the special diet recommended and used by them (462): 

The daily requirements of the diet in order of assumed 
importance are: 

(1) Liver (calves, beef, chicken) or kidneys (lamb) 
freshly cooked. At least one hundred and twenty, 
preferably two hundred or more, grams (cooked 
weight). Cook without fat; broil, bake, boil, 
mince or make into soup. 

(2) Fruits, preferably fresh—especially peaches, apri- 
cots, pineapple, strawberries, oranges, and grape- 
fruit—about four hundred grams. Raisins are de- 
sirable; allow them to be eaten freely. 

(3) Red muscle meat, trimmed free of fat, freshly 
cooked; one hundred and twenty-five grams or 
more. Beef heart is desirable. 


PROPHYLAXIS AND TREATMENT = 237 


(4) Vegetables containing one to ten per cent of car- 
bohydrates, preferably fresh; cooked or raw. Not 
less than three hundred grams. Lettuce, spinach, 
asparagus, cabbage, and tomato are especially 
desirable. 

(5) Fats restricted, not over seventy grams. Avoid 
cheese, bacon, fried food. Allow but little cream 
and butter and not over one egg. Use mineral oil 
for salad dressings. 

(6) Avoid grossly sweet foods, yet allow sugar 
sparingly. 

(7) Starchy foods, as cereals, potato, breads, add to 
suit individual desires, but not to the exclusion of 
the requirements given above. The starchy foods 
are best crusty or dextrinated. Whole wheat toast 
is desirable. 

(8) Milk is best limited to about two hundred and 
forty grams. 

(9) Avoid excess of salt. Tea and coffee as desired. 

Ideally all food should be weighed. The liver is essential 
and must be weighed at first. After the patient under- 
stands the approximate quantity of the different foods to 
be taken their amounts may be estimated. 

The food must be palatable and as attractive as possible. 
The art of fine cooking and serving combined with per- 
suasion will often be necessary to get the patient to eat 
the food desired. 

Several small meals a day rather than three may be 
found suitable. The exact condition and desires of each 
patient must never be neglected; for instance, a persistent 
diarrhoea may necessitate that less fruit be eaten and that 
vegetables be pureed; allowing the patient his choice of 
the form or type of required food may enhance his 
progress. 

When the patient is unable to take much food, it is 
important that he eat some liver or kidneys (chicken giz- 


238 PERNICIOUS ANEMIA 


zards may be substituted) and fruit, even if no other food 
is taken. Then gradually add meat and green vegetables. 
The starchy foods are to be given in accordance with the 
amount of the other foods eaten. The patient should be 
expected to take the full diet within about two weeks after 
commencing it. 

Present information suggests that the patient should 
continue with this sort of diet even though his red blood 
cell count remains high. 

The full diet should contain for the average person 
about two thousand five hundred calories, the protein 
being about one hundred and thirty-five grams, the car- 
bohydrate about three hundred and forty grams, and the 
fat not over seventy grams. This is the approximate com- 
position of the food given in the sample menu below. 


BREAKFAST 
Approximate weight in grams 

Liver or kidneys, broiled... 100 
Oatmeal, 2 heaping tablespoons cooked, or dry meal...............- 18 
Milk, '3) tablespoons... 00. tn ee 45 
Sugar, 2 level teaspoonss../..-).0.002..0. 10 
Toast, 3 slices (each slice 4 x 2 x,34 inches)... 30 
Butter, 1 level teaspoon or a piece l x1x¥&% inches Meee |, 5 
Fruits, choice of 

(a) Orange, average ‘sizéeinic. 0 120 

(b) Strawberries, 534 tablespoons...-...2..-. eee Pi) 

(c) Grapefruit, 4 of one very large one... 200 

(d) Peach, 1 large one)..e2..) eh 120 

DINNER 

Beef, steak or roast, trimmed of fat; a very large serving........ 120 
Vegetables, freshly cooked, as spinach, string beans, cabbage, 

tomato, etc., 2 average portions or 5 to 8 tablespoons............ 250 
Potato, baked, medium size...) .020. le LAZO 
Bread, 2 slices (each slice 3 x 4.x 14 inches)... eee 70 
Salad, pineapple, 214 slices, of size In Cans..071..20 1.23 eee 140 
ettuce, big “helping...02/0..0 a 75 
Pudding made of 

(1) Gelatine, 1 teaspoon, dry) weight. 2:../2.75. 2 eee 2 

(2) Rice, boiled, 2 heaping tablespoons...1..2.-...2 22 eae 160 


(3) Raisins, 20 large omes.(20 6.2 50 


PROPHYLAXIS AND TREATMENT 239 


(CRU Fs 2402212) CC 0°09) 0 ee 30 
(Fruits may be put into such a dessert and raisins eaten 
separately.) 

SUPPER 
Liver soup, composed of 
(Tp TLANWE ESTAR EG Ie SEE Ee eee ee Sen 100 
(A) WI 152 51g gb) 517211) 85 | UE A eee en SCE CARO EP 220 
oie atte eC volte ih TEASPOON. anna oe k o ee cece ch ce cee + 
(4) Butter, 1 rounded teaspoon or a piece 1 x 1 x % in....... 10 
Lamb, roast, without fatty parts, 2 small slices....................-.---- 60 
JING oy ii oor era AS fh £15) (cS 0.010) 1 Ye Rea ne 150 
or 
Potato, a small one, or rice, 1 heaping tablespoon.................... 80 
Vegetables, fresh, 2 average portions, 5 to 8 tablespoons........ 250 
RPE DISCINE OF EFISCUIL, Ae i<oo50 ek hades Snot eee hed een 25 
Butter, 1 level teaspoon or a piece 1 x 1 x Y inches.................. 5 
Choice of 
ee SiiaWNEEIES, 7, TADIESPOONS ic. 55.) ee tech et ae 225 
Py OAD Ces a ARSE OME 24 i sh abel las eee ao see aa ats aaa 150 
(c) Apricots, or prunes, stewed, 2 tablespoons................----.- 100 
pS) lecenpme ZN avery ey gn Ret Oc 0 * Saas nna ee 20 


A vegetable soup could be taken in place of the liver 
soup and the liver eaten in the following form: Mince it 
and mix with rise or potato and the allowance of butter, 
and stuff into green peppers. 

The following menu gives an example of a suitable diet 
for a day with fewer calories than that given above. The 
food listed contains about two thousand five hundred 
colories, derived from about one hundred and fifteen 
grams of protein, sixty-five of fat, and two hundred and 
fifty of carbohydrate. 


BREAKFAST 

Fruit, choice of 
(2)Orance juice, from’ Z oranges. 2.20 seer eee 130 
(bp) Grapetrint, 1 whole, medium size. 22. 240 
(ey) Strawberries, 534 tablespoons.i1. i) ee a 180 
pmuctucmany meat, 1 biseiit so): 15 ee a ino 30 
RRP BtA DIES DOONS o-oo ca tenet ne coe an eas ee a cata 30 
mime VelteaSpOOI ck. cesects a Cree EDs 2 ts 5 
Beet, minced; Z heaping tablespoons... 4.4.0. 75 
Grean, 20 per cent, 4 tablespoons. seit) cle inte scenes nore 60 
Maas 2ysitees (each slice 4 x 2x34 inches)... 20 


Butter, 1 rounded teaspoon or a piece 1 x 1 x % inches.......... 10 


240 PERNICIOUS ANEMIA 


LUNCHEON 
Liver, broiled... ec 120 
Lettuce or cold slaw, large helping._................__....2aee 80 
Potato, cold, ‘sliced, or baked, hot! 1 small... eee 80 


Tomatoes, stewed, 5 tablespoons, or raw, 2 of medium size.... 150 
Cauliflower or Brussells sprouts, an average portion or 


three tablespoons. «....2s..02.-20<cibeessteeseenecnd se s<eneen 0 err 130 
Zwieback,, 2 PieCeS. 200 lo soe a cac ened aeacecensnee- err 30 
Butter, 1 level teaspoon or a piece 1 x 1 x Y% inches... 
Apricots, stewed, 3 heaping tablespoons............--..----.-1e.----00-0000-« 120 

DINNER 
Soup, consomme (any amount desired) mixed with sieved 

liver (flavor with spice) q.0.222.2:2022.2,..2..<...01... 75 
Mutton, 2 large slices, trimmed of fat............--......eee 100 
Beets or peas, 3 tablespoons... 0-2-2. --c-<-:ese--<+-- eer 100 
Potato, boiled, average size.)./....2.-2...--)___... 130 
Spinach, or string beans, an average portion or 

3 to 5 tablespoons. ..20.-.2..-3.520.0. 0-0) 150 
Butter, 1 level teaspoon or a piece 1 x 1 x Y inches.................. 5 
Toast, 2 slices (each slice 4.x Z x ‘4 inches) ..22. eee 20 


Blanc mange, 2 heaping tablespoons (made of % cup Irish 
moss, 2 cups milk, 1 tablespoon 20 per cent cream, 2 


tEASPOONS SUPAL) ooo anes a cease cnet ee ecee nena 100 
Blueberries, 5 tablespoons, or applesauce, with 1 level 
teaspoon (5 grams) of sugar, 2 tablespoons...........-----.---.+« 80 


(Fruit may be mixed with blanc mange.) 


A more recent report by Murphy, Monroe, and Fitz 
(463) states that since the first report was published, 
Minot and Murphy have found that in order to obtain 
good results, it is unnecessary that the protein intake of 
the diet should be as great as that recommended in the 
above instructions. This report gives further information 
on the results of this treatment. 

A constant result is a temporary increase in the number 
of circulating reticulocytes. Before treatment a fraction 
of one per cent is usually found. Within from four to ten 
days after treatment there begins a very rapid increase, so 
that within two or three days a peak of six to fifteen and 
five-tenths per cent is reached. This peak is only main- 
tained for a day or two, when the count rapidly declines, 


PROPHYLAXIS AND TREATMENT 241 


then more slowly, so that it reaches its pre-treatment level 
by the second or third week. These authors do not mention 
any increase in nucleated red blood cells as accompanying 
this reticulocyte “bump.” 

The icterus index drops very quickly even within the 
first week of treatment, and has reached the level of nor- 
mal range by the end of the second week, or actually gone 
below this level. 

These evidences of blood regeneration and of pig- 
ment change occur simultaneously and their coincidence 
strongly suggests that the newly formed red corpuscles 
are able to use up excess of hemoglobin-derived pigments. 

Reference has already been made to the remarkable 
disappearance of anisocytosis, demonstrated by Medearis 
and Minot (427) in the blood of patients during liver- 
diet remissions. 

Minot has recently reported success in extracting from 
liver a substance or substances which when given in as 
small amounts as ten grams per day causes similar blood 
improvements. This suggests that this form of treatment 
is an instance of organotherapy. 

It has been suggested by Simmonds et al. (579) that the 
beneficial effect of liver is due to a combination of two 
factors—its high food iron content and the presence in it 
of Vitamine E. 

Whatever the explanation may prove to be, one fact is 
now evident, that the feeding of liver is the best treatment 
available for pernicious anemia, and that the effects of 
this treatment, as judged by the reaction of the marrow, 
the sudden normal behavior of the pigments, and the 
eventual improvement in cellular morphology, constitute 
the most dramatic phenomena observed at any time in 
connection with this disease. Such specific readjustment 
within the organism suggests that this treatment touches 
the disease close to its etiological point. 


AUTHOR-SUBJECT INDEX OF BIBLIOGRAPHY 
CONSIDERED 


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[ 242 ] 


BIBLIOGRAPHY 243 


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248 PERNICIOUS ANEMIA 


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BIBLIOGRAPHY 255 


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256 PERNICIOUS ANEMIA 


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(673) A contribution to the etiology of pernicious anemia. Pilcher, 
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(676) Anemia in hypothyroidism. Mackenzie, G. M.: Jour. Amer. 
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Association of pernicious anemia with subacute combined 
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A unique case of pernicious anemia. Tidy, L.: Lancet, 1922: 
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Autogenous vaccines in pernicious anemia. Hurst and Bell: 
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Bacterial cultures of human spleens removed by surgical 
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Blood fats and lipoids of dog before and after production 
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Blood metabolism in pernicious anemia. Sonnenfeld, A.: 
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Blood regeneration. Eddy, N. B., and Downs, A. W.: Can- 
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Blood transfusion in pernicious anemia. Gotling, H.: 
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Bone-marrow metastases and anemia in gastric cancer. 
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Cancer in pernicious anemia. Sonnenfeld, A.: Deutsche 
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Case of pernicious anemia of aplastic type with phagocy- 
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Cholesterol content of blood in anemia and its relation to 
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Cholesterin in blood and resisting power of red blood cells 
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Chronic carbon monoxide poisoning—2 cases simulating 
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(698) Colon bacilli in digestive tract especially with regard to 
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(702) Diagnosis: recent advances in hematology: laboratory aids 
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(706) Disturbance of central nervous system accompanying per- 
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Effect of whole blood transfusions on the cholesterol con- 
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Endocrine glands in pernicious anemia. Menderschausen, 
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Familial and constitutional factor in pernicious anemia. 
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General aspect of early diagnosis of pernicious anemia. 
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Hemolytic jaundice and pernicious anemia. Maas, J.: Mitt. 
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Hypertrophy of pylorus in pernicious anemia. Mayeda, T.: 
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Hypernephroma with hemolytic anemia. Lenaz, L.: Ri- 
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Infantile splenic anemia. Ramsay, G. W. St. C.: Brit. Jour. 
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Infectious anemia of the horse in man. Peters, J. T.: 
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Influence of splenectomy on pernicious anemia. v. Decas- 
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Interesting case report. Andrews, C.: Jour. Med. Soc., 
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Intestinal origin of pernicious anemia. Julich, W.: Med. 
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Metabolism of erythrocytes in anemia. Denecke, G.: Deut- 
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L. H.: Amer. Jour. Med. Sci., 1914: CXLVIII, No. 3. 

Observations on treatment. Colwell, A. A.: Pennsylvania 
Med. Jour., 1923: XXVI, 232-234. 

Oral sepsis and the anemias. Graves, M. L.: Southern Med. 
Jour., 1918: XI, 484. 


292 
(742) 


(743) 
(744) 
(745) 
(746) 
(747) 
(748) 
(749) 
(750) 
(751) 
(752) 
(753) 


(754) 


(755) 


(756) 


(757) 
(758) 


(759) 


PERNICIOUS ANEMIA 


Oral sepsis in relationship to septic anemia. Hunter, W.: 
Practitioner, 1914: XCIII, No. 2. 

Osteosclerotic anemia. Bernhardt, H.: Klin. Wehnschr., 
1926: V, 415-417. 

Osteosclerotic anemia. Reiche, F.: Munchen. med. Wchn- 
schr., 1915: LXII, No. 28. 

Pathogenesis of pernicious anemia. Autor. Deutsche med. 
Wehnschr., 1923: LX XX, 1034. 

Pathogenesis of pernicious anemia. Moses, A., and War- 
schner, B.: Klin. Wchnschr., 1923: II, 581-584. 

Pathology of pernicious anemia. Barrow, M.: Lancet, 
1915: XXXV, No. 16, Aug. 15. 

Pernicious anemia. Kulcke, E.: Munchen. med. Wchnschr., 
1923: LXX, 803-805. 

Pernicious anemia. Roth, O.: Leitschr. f. klin. Med., 1914: 
LXXIX, Nos. 3 and 4. 

Pernicious anemia and gastric acidity. Med. Klin., 1924: 
XX, 1649. 

Pernicious anemia as studied through a remission. Grieg 
and Dennis: Colorado Med., 1922: XIX, 125. 

Pernicious anemia: dietary treatment. Brill, I. C.: North- 
west. Med., 1926: Dec., No. 25. 

Pernicious anemia from thorium. Emile-Weil, P.: Bull. de 
la Soc. Méd. d. Hop. d. Paris, 1926; L, 1627. 

Pernicious anemia: gastrointestinal and spinal cord symp- 
toms. Mohler, H. K.: Med. Cl. of N. Amer. 1921: Jan., 
1239. 

Pernicious anemia in a girl of fourteen. Condat, Mlle.: 
Arch. d. med. d. enf., 1921: XXIV, 676. 

Pernicious anemia in exophthalmic goitre after roentgen 
treatment, Hansen, I.: Ugesk. f. Laeger., 1922: 
LXXXIV, 1643. 

Pernicious anemia in purpura. Posse, C. B., and Guerra, 
R. R.: Rev. Med. d. Uruguay, 1922: XXV, 798-801. 
Pernicious anemia in two brothers. Johannessohn, F.: 

Deutsche med. Wehnschr., 1925: LI, 1953-1954. 

Pernicious anemia of pregnancy. Signorelli, E.: Riforma 

Med., 1920: XXXVI, 624. 


(760) 


(761) 


(762) 


(763) 


(764) 
(765) 
(766) 
(767) 
(768) 
(769) 
(770) 
(771) 


(772) 


_ (773) 
(774) 


(775) 


BIBLIOGRAPHY 293 


Pernicious anemia treated by mercurochrome. McLaugh- 
line Bs ben otatry, A. C. and McHugh, C: P.: Jour. 
Iowa State Med. Soc., 1925: XV, 6. 

Pernicious anemia treated by multiple transfusion and 
splenectomy. Schisler, E.: Jour. Missouri Med. Asscn., 
1918: XV, 392-394. 

Pernicious anemia treated by splenectomy and systematic, 
often-repeated transfusion of blood. McClure: Jour. 
Amer. Med. Asscn., 1916: LXVII, 793. 

Pernicious anemia with ataxoparaplegic syndrome. Thomas, 
A., and Poix, G.: Arch. d. Mal. du Coeur, 1922: XV, 
481-486. 

Pernicious anemia with free HCl: case report. Taubmann, 
G.: Deutsches Arch. f. klin. Med., 1926: CL, 309-314. 

Plasma chlorides in anemia. Steinfield, E.: Arch. Int. Med., 
1919: XXIII, 511. 

Plasma lipoids in experimental anemias. Bloor, W. R.: 
Jour. Biol. Chem., 1925: LXIII, 1-15. 

Pregnancy in relation to pernicious anemia. Heim, K.: 
Centralbl. f. Gynak., 1923: XLVII, 818-824. 

Present status of treatment of pernicious anemia. Mc- 
Laughlin, P. B.: Jour. lowa State Med., 1922: XII, 6. 

Primary pernicious anemia. Mikhailoff, M. P.: Russky 
Vrach., 1914: No. 24, June 27. 

Prognosis in pernicious anemia. Ladek, I.: Munchen. med. 
Wehnschr., 1924: LXXI, 940-942. 

Progressive pernicious anemia. Griswold, W. S., and 
Heussy, W. C.: Northwest Med., 1918: XVII, 105-110. 

Protective power of serum in pernicious anemia against 
hemolysis by saponin and by sodium oleate. Zinck, R. 
H., Clark, H. M., and Evans, F. A.: Bull. Johns Hop- 
kins Hosp., 1922: XX XIII, 16-21. 

Protein therapy in pernicious anemia. Faber, K.: Presse 
Méd., 1922: XXX, 873-876. 

Psychosis in pernicious anemia. Williams, G. H.: Jour. 
Amer. Med. Asscn., 1914: Sept. 12. 

Radium treatment of pernicious anemia. Tomanek, F.: Cas. 
lek. Ask., 1924: LXIITI, 549-552. 


294 
(776) 


(777) 


(778) 


(779) 


(780) 


(781) 


(782) 


(783) 
(784) 


(785) 


(786) 


(787) 
(788) 
(789) 


(790) 


PERNICIOUS ANEMIA 


Relations between gastric achylia and simple and perni- 
cious anemia. Faber, K., and Gram, H. C.: Arch. Int. 
Med., 1924: XXXIV, 658. 

Relation of pernicious anemia to carcinoma of stomach. 
Brandes, T.: Med. Klinik, 1921: XVII, 189. 

Relation of some hemolytic disorders to pernicious anemia. 
Panton, P. N., Maitland-Jones, A. G., and Riddoch, 
G.: Lancet, 1924: I, 529-533. 

Relationship of infection in the production of so-called per- 
nicious anemia and its significance with respect to treat- 
ment. Smithies, F.: Med. Record, 1918: XCIII, 172- 
174. 

Repeated small injections of blood in pernicious anemia. 
Waag, A.: Miinchen. med. Wchnschr., 1921: LXVIII, 
677. 

Report of a case of bothriocephalus anemia. Schmidt, H. 
B.: Jour. Michigan Med. Soc., 1916: XV, 248. 

Retention of iron in organs in hemolytic anemia. Muir, R., 
and Drum, J. S.: Jour. Path. and Bact., 1915: XIX, 
417-428. 

Retinal hemorrhages in bothriocephalus anemia. Cohen, M.: 
Arch. Ophth., 1924: LIII, 362-367. 

Results of treatment in pernicious anemia. Bloomfield, A.: 
Bull. Johns Hopkins Hosp., 1918: XXIX, 101. 

Secretin : its effect in anemia with note on supposed simi- 
larity between secretin and vitamin B. Downs, E. W., 
and Eddy, H. B.: Amer. Jour. Physiol., 1921: LVIII, 
296. 

Severe anemia connected with gastro-intestinal disease. 
Schmidt, A.: Amer. Jour. Med. Sci., 1914: CXLVIII, 
No. 3. 

Small intestine and pernicious anemia. Seyderhelm, R.: 
Klin. Wchnschr., 1924: III, 568. 

Some cases of aleukia or aplastic anemia associated with 
thrombopenia. Dyke, S. C.: Lancet, 1924: I, 1048-1051. 

Spleen as a factor in anemia. Turk, W.: Deutsche med. 
Wehnschr., 1914: XL, 371-376. 

Splenectomy for pernicious anemia. Moorhead, FE. L.: Sur- 
gical Clin., 1918: II, 785. 


(791) 
(792) 
(793) 
(794) 
(795) 
(796) 


(797) 


(799) 


(799) 


(800) 


(801) 


(802) 
(803) 
(804) 
(805) ° 


(806) 


(807) 


BIBLIOGRAPHY 295 


Splenectomy in pernicious anemia. Holm, E.: Ugest. f. 
Laeger., 1922: LX XXIV, 1781-1785. 

Splenectomy in pernicious anemia. Jagic: Wien. kin. 
Wehnschr., 1914: X XVII, 1356. 

Splenectomy in pernicious anemia. Krumbhaar, E. B.: Jour. 
Amer. Med. Asscn., 1916: LXVII, 723. 

Splenectomy in pernicious anemia. Penrose, C. A.: South- 
ern Med. Jour., 1915: VIII, 10. 

Splenectomy in pernicious anemia. Part, F.: Berl. klin. 
Wehnschr., 1914: 12, Mar. 13. 

Splenectomy in pernicious anemia. Splendler, G.: Wien. 
klin. Wchnschr., 1920: XX XIII, 86. 

Splenectomy in pernicious anemia with studies on bone 
marrow stimulation. Lee, R. I., Minot, G. R., and Vin- 
cent, B.: Jour. Amer. Med. Asscn., 1916: LXVII, 719. 

Sprue and pernicious anemia. Bramwell, B.: Brit. Med. 
Jour., 1924: I, 365-366. 

Storage of radium and mesothosium in reticulo-endothe- 
lium. Maitland, H. S., Conton, P., and Knef, J. P.: 
Jour. Amer. Med. Asscn., 1925: LXXXV, 1769-1776. 

Studies in pernicious anemia. Moffit, H. C.: Amer. Jour. 
Med. Sci., 1914: CXLVIII, 817-827. 

Study of nervous syndrome and blood serum in pernicious 
anemia as an aid in diagnosis, etc. Riggs, C. E.: Minne- 
sota Med., 1924: VII, 484-495. 

Symptomatology reviewed. Strieck, F.: Med. Klinik, 1924: 
XX, 1538. 

Syphilis and grave anemia. Hoff, F.: Deutsches Arch. f. 
klin. Med., 1924: CXLIV, 297-305. 

The anemia of cancer of the gastro-intestinal tract. Eisen, 
D.: Canadian Med. Asscn. Jour., 1927: XVII, 307-313. 

The blood and the endocrines. Londek, H., and Koehler, 
G.: Klin. Wchnschr., 1926: V, 876-881. 

The importance of the dissolving of the worm in bothrio- 
cephalus anemia. Saltzman, F.: Acta Med. Scandinav., 
1924: Suppl. 7., 268-272. 

The pernicious anemia of pregnancy. Gram, H. C.: Ugest. 
f. Laeger., 1920: LX XXII, 1609. 


296 PERNICIOUS ANEMIA 


(808) The relation of foci of infection to grave anemias. Rinker, 
F. C.: Virginia Med. Monthly, 1920: XLVII, 147. 

(809) The Robert Campbell Oration on Addison’s anemia. Hous- 
ton, T.: Medical Press, 1924: CX VIII, 449. 

(810) The significance of acro-ataxia and proximo-ataxia. Hoov- 
er, C. F.: Amer. Jour. Med: Sci., 1915:Gi@aie 

(811) The treatment of pernicious anemia. Wales, H. C.: Cana- 
dian Med. Asscn. Jour., 1927: XVII, 397-400. 

(812) The treatment of pernicious anemia by splenectomy. Giffin, 
H. Z., and Szlapka, T. L.: Jour. Amer. Med. Asscn., 
1921: LXXVI, 290. 

(813) Transfusion from donor with plethora. Weill, P. E., and 
Stieffel, R.: Bull. d. 1. Soc. Med. de. Hép. d. Paris, 
1925: XLIX, 1454. 

(814) Transfusion in pernicious anemia. Muller, C., and Jerrel, 
F.: Norsk. Mag. f. Laeger., 1921: LX XXII, 442. 

(815) Transfusion of blood in pernicious anemia. Bon, C. J. 
Nederlandsch. Tijdschr. v. Geneesk., 1921: I, 2793. 

(816) Transfusion of blood in pernicious anemia. Graham, J. M.: 
Edin. Med. Jour., 1920: XXIV, 282. 

(817) Transfusion of blood in pernicious anemia. Host, A. F.: 
Norsk. Mag. f. Laeger., 1922: LXXXIII, 103-117. 

(818) Transfusion of blood in pernicious anemia. Savolin, M.: 
Finska Lak.—Sallk. Handl., 1922: LXIV, 591-615. 

(819) Transfusion of small quantities of blood in treatment of 
pernicious Anemia. Walter, K.: Miinchen. med. Wchn- 
schr., 1924: LXXI, 866-867. 

(820) Trauma of nervous system and pernicious anemia. Zadek, 
I.: Munchen. med. Wchnschr., 1920: LX VII, 960. 

(821) Treatment by intramuscular blood injections. Zetterquist, 
A.: Svenka. Lak.-Sallsk. Handl., 1924: L, 1-16. 

(822) Treatment of anemias with colloidal metals. Aschner, B.: 
Wein. Arch. f. inn. Med., 1923: V, 523-542. 

(823) Treatment of pernicious anemia by transfusion and splen- 
ectomy. Minot, G. R., and Lee, R. I.: Boston Med. and 
Surg. Jour., 1917: CLXXVII, 761. 

(824) Treatment of pernicious anemia with HCl and arsenic. 
Bohan, P. T.: Jour. Missouri State Med. Assen., 1922: 
XIX, 451. 


BIBLIOGRAPHY 297 


(825) Unclassified anemia with thrombopenia and leukopenia. 
Cabot Case 12343: Boston Med. and Surg. Jour., 1926: 
CXCV, 434-440. 

(826) Undernutrition and disease, especially atypical forms of 
pernicious anemia. Bittorf, A.: Minchen. med. Wchn- 
schr., 1923: LXX, 419-421. 

(827) X-ray treatment of pernicious anemia. Haggeney, P.: Med. 
Klinik, 1922: XVIII, 1141-1142. 





INDEX 


Abdominal crisis, 101, 226. 
Abiotrophy, 61. 
Abscess, apical, 217. 
Absorption, of food, 183. 
disturbed, 106. 
Absorption bands, 162. 
Acetanilid, 77. 
Achlorhydria, 44-54. 
absent, 46. 
alcoholic, 47. 
alkaline tide in, 53. 
anemia due to, 216. 
causes of, 48. 
chloride ions in, 190. 
consequences of, 53. 
definition of, 50. 
diagnostic value, 215, 216. 
early appearance of, 46. 


experimental production of, 52. 


following operations, 47. 
in anemia of pregnancy, 223. 
in cachexia, 52. 
in cord degeneration, 46. 
in sprue, 222. 
in various conditions, 52. 
incidence in health, 53. 
influence on digestion, 184. 
intestinal flora in, 53. 
pancreatic function in, 53. 
permanency of, 47. 
recovery from, 46. 
relation to disease, 54. 
types of, 47. 
Welch bacillus, and, 71. 
with cancer, 47. 
Achlorhydric anemia, 52. 
Achromia, 146. 
in anemia of pregnancy, 223. 
in cancer anemia, 219. 
Achylia gastrica, 44, 50. 
of old age, 14. 
Acid 
hydrochloric, 228, 231. 
linolenic, 187. 
oleic, 77, 186, 187. 
oxyproteic, 184. 
uric, 184. 
Acids, fatty, 184, 186. 


Aciduric cultures, 201, 229, 231. 
Acromegalic characters, 60, 80. 
Acro-ataxia, 203. 
Acute pernicious anemia, 122. 
Acute yellow atrophy, 186. 
Addison, death of, 22. 
Addison’s disease, 18, 225. 
Adrenotropes, 59. 
Agglutinins, 174. 
Agonal crisis, 158. 
Albumin 
in urine, 211. 
of serum, 189. 
Albiminuria, 25. 
Alcoholism, 81, 104. 
Alkaline tide, 189. 
Alveolar air, 189. 
Ammonia, 184. 
Amino-acids, 189. 
Amylase, 110. 
Ancestral cells, 125. 
Anemia 
Addison’s, 5. 
Addison-Hunterian, 5. 
aplastic, 4, 182, 225. 
Biermer, 5. 
Biermer-Ehrlich, 5. 
bothriocephalus, 4, 186. 
B. Welchii, 70. 
D. Latus, 163. 
dibothriocephalus, 4, 186. 
dyscrasic, 5. 
dysformative, 5. 
dysharmonic, 5. 
dystrophic, 5. 
erythrohyperplastic, 5. 
erythroplastic, 5 
essential, 5, 21. 
experimental, 76, 182. 
fish tape-worm, 4. 
from benzol, 182. 
from hemorrhage, 163. 
from mesothorium, 225. 
from radium, 225. 
hemolytic of pregnancy, 4, 223. 
from toluylendiamin, 186. 
hemomyelotoxic, 4. 
hemopathic, 4. 


[ 299 ] 


300 


Anemia (Cont.) 
hemorrhagic, 4. 
hemotoxic, 4. 
hyperchromic, 4. 
hypochromic, 4. 
idiopathic, 5, (glossitic) 5. 
infantile, 13. 
in polycythemia, 225. 
lethal, 5. 
macrocytic, 29, 65. 
megaloblastic, 32. 
myelopathic, 4. 
myelotoxic, 5. 
normoblastic, 32. 
of achlorhydria, 52, 216. 
of aleukemic leukemia, 64. 
of ankylostomiasis, 16. 
of balantidium coli, 64. 
of carcinoma, 23. 
of colonic cancer, 64. 
of fish tape-worm, 64. 
of gastric carcinoma, 

218-220. 
of hookworm, 4. 
of indigestion, 216. 
of malaria, 23. 
of malignant marrow, 64. 
of myxedema, 226. 
of osteosclerosis, 225. 
of pregnancy, 4, 64. 
of puerperal sepsis, 17, 223. 
of sepsis, 216. 
of sprue, 4, 64. 
of syphilis, 4, 64. 
pernicious, 5. 
acute form, 122. 
aplastic form, 122. 
chronic intermittent, 122. 
recovery from, 46. 
types, 121-122. 

primary, 5. 
progressive, 23. 

secondary, 5. 

septic, 16, 27. 

simple, in pregnancy, 223. 

splenic, 226. 

“stricture,” 81, 109. 
Anemias, similar, 63. 
Anasarca, 207. 

Anesthesia, 203. 

Angina pectoris, 208. 


4, 64, 


PERNICIOUS ANEMIA 


Aniline, dyes, 29. 

poisoning, 224. 
Anisochromia, 146. 
Anisocytosis, 35, 140-145. 

experimental, 127. 

in sprue, 222. 

mild, 140. 

under liver diet, 144. 

variations, 141. 

without anemia, 140. 
Ankle jerks, 203. 
Ankylostomiasis, 163. 
Ankylostomum, 112, 186. 
Annular degeneration, 204. 
Anoplocephaline cestodes, 186. 
Anorexia, 24, 25, 88, 99. 
Antihemolytic substance, 187. 
Antimony, 228, 230. 
Antisyphilitic drugs, 229. 
Antithrombin, 181. 
Antitoxin, B. Welchii, 70, 228, 

230. 
Aorta, atheroma of, 208. 
Apathy, 205. 
Aphasia, 25. 
Aplastic anemia, 225. 
Aplastic form, 122. 
Appearance of patient, 17, 115. 
Appearance time, of  merve 
changes, 200. 

Appendicitis, 84, 217. 
Appetite, 17, 19, 24, 25, 120. 
Apprehension, 205. 
Arneth index, 150, 154. 
Arsenic, 27. 
Arteriosclerosis, 208, 209, 225. 
Arthralgia, 84. 
Arthritis, 52, 120, 140. 
Ascaris, 112. 
Ascites, 124. 
Ash of blood, 189. 
Astereognosis, 203. 
Asthenia, 18. 
Asthma, 120. 
Ataxia, 118, 195. 

in locomotion, 203. 
Atoxyl-resistant lipase, 192. 
Atheroma, 208. 
Atony, 110. 
Atrophy 

of bone, 133. 


INDEX 


Atrophy (Cont.) 

of astric glands, 103. 

of gastric mucosa, 34, 44. 

of intestine, 44, 104. 

of liver, 186. 

of spleen, 136. 

of stomach, 106. 
Atrophy, primary, 104, 106. 
Autoagglutination, 174. 
Autointoxication, 67. 
Autolytic products of cancer, 219. 


Bacillus, coli, 69, 74, 101, 111, 
230 


paratyphosis, 192. 

proteus, 

typhosus, 75, 192. 

Welchii, 69, 70, 71, 111, 230. 
Bacterial content, spinal fluid, 198. 
Balance, acid-base, 189. 

nitrogen, 184. 

Balantidium coli, 77, 112. 
Banti’s disease, 226. 
Basal metabolism rate, 193, 194. 

in myxedema, 226. 
Basophilia, 131. 

in spleen, 137. 

Bed sores, 203. 
Belching, 84. 
Benzol, 182, 224. 
Bile 

bilirubin in, 164. 

drainage, 228. 

pigments, 36, 158. 

salts, 189, 198. 

staining, 114. 

Bilirubin, 36, 40, 164-174, 194. 
Bladder 

disturbance of, 204. 

hemorrhage in, 208. 

innervation of, 212. 

Blasts, 156. 
Blast crisis, 35, 149, 158. 
Bleeding 

in treatment, 228. 

time, 181. 

uterine, 81. 

Blood 

amount of, 139. 

arterial, oxygen in, 182. 
Blood changes, histological, 122. 
Blood, chemistry of, 188-191. 
Blood counts, 115, 153. 


301 


Blood corpuscles, 34. 

Blood cultures, 225. 

Blood destruction, 4, 40, 124, 128, 

13150: 
by fatty acids, 187. 
factors of, 152. 
in liver, 138. 
in lymph glands, 138. 
mechanism of, 38. 
portal, 33, 163. 
rate of, 35. 
role of, 153-154. 

Blood fats, 187, 188. 

Blood formation, abnormal, 31, 35. 
embryonic type, 123. 
extra-medullary, 13, 128, 138, 

139. 
reversion of type of, 29. 

Blood groups, 174. 

Blood, human in treatment, 228. 

Blood infection, 72. 

Blood platelets, 35, 150, 223, 225. 

Blood phenols, 192. 

Blood pigment, 158. 

Blood picture 
diagnosis by, 140. 
of old age, 14. 
onset of, 216. 

“pernicious,” 64. 
typical, 139. 

Blood pictures 
abortive, 116. 
and incurrent disease, 116. 
experimental, 71, 77, 127, 128. 
identical, 64. 
terminal, 116. 

Blood pressure, 210, 212. 

Blood production, 35, 150, 151. 

Blood proteins, 188. 

Blood regeneration 
by diet, 234. 
rate of, 153, 154. 

Blood sinuses, 138. 

Blood state, in remissions, 118. 

Blood system, functional state, 
150. 

Blood transfusion, 27, 232. 
effect on basal rate, 193-4. 
effect on bilirubinemia, 168. 
effect on metabolism, 184. 
effect on prothrombin, 182. 
effect on retinal hemorrhage, 

214. 


302 


Blood volume, 175-177. 
influence on counts, 154. 
influence on ear symptoms, 214. 

Bone-marrow 
antithrombin and, 182. 
aplastic areas in, 132. 
compensatory hyperplasia of, 30. 
changes in remissions, 41. 
depression of, in pregnancy, 

224. 
disease of, 125. 
excochleation of, 233. 
experimental spread, 151. 
extension of, 40, 132, 133. 
function of, 128. 
fibrinogen and, 182. 
histology of, 41. 
hyperplasia of, 125, 132. 
in endocarditis, 124. 
in hemolytic jaundice, 225. 
in pneumonia, 124. 
in septic anemia, 224. 
in treatment, 231. 
in tuberculosis, 124. 
in typhoid, 124. 
productive, 151. 
phagocytosis, 37. 
reactions, 127. 
red, 40, 123. 
sarcoma of, 124. 
siderosis of, 41. 
states of, 155-158. 
toxins and, 127. 
various bones of, 129, 130, 135. 

Bone-marrow picture, 124, 135. 

Bone-marrow state, 154, 155. 

Bowels, movements of, 16. 

Brain, 196. 

Breathlessness, 19. 

Bruits, 24. 

Bronzing, 115. 

Buccal mucosa, 98. 

Burning, 202. 

Buttermilk, 229. 


Cabot bodies, 134, 149, 157. 
Cachexia, 125. 

of gastric cancer, 183. 

of old age, 14. 

of syphilis, 183, 221. 
Cacodylate of sodium, 229. 


PERNICIOUS ANEMIA 


Caecum, 105. 
Calomel, 228. 
Calorimetry, 193. 
Cancer of stomach, 123, 169, 218- 
220. 

Capillaries, 115. 
Carbohydrate metabolism, 188. 
Carbon dioxide, 189. 
Carcinoma, 123. 
Cardiac hypertrophy, 209. 
Cardiac dilatation, 209. 
Cardiac dullness, 24. 
Cardiac insufficiency, 169. 
Cardiac pain, 208. 
Case history, 80. 
Castor-oil soaps, 175. 
Catalase, 191-192. 
Cavity formation in cord, 197. 
CharcoalyZoz. 
Chemistry of blood, 174, 188. 
Cheyne-Stokes respiration, 206. 
Chloride metabolism, 190. 
Chlorosis, 16, 21, 214. 
Cholesterinase, 192. 
Cholesterol 

of blood, 187, 188. 

of cystic bile, 101. 

in treatment, 231. 
Chlosterol oleate, 186. 
Cholecystitis, 84, 100, 217. 
Cicatrices of ulcers, 105. 
Circulation, 182. 
Clasmatocytes, 37, 41, 128, 134, 

1152: 


Classification of anemias, 3, 4. 

Clinical types, 86. 

Clonus, 203. 

Clot, post-mortem, 16. 

Coagulation factors, 181. 

Coldness, 202. 

Colitis, 108. 

Colloidal iron, 230. 

Color index, 160, 217. 

Colon 
disease of, 110. 
distention of, 109. 
flora of, 111. 
inflammation of, 108. 
irrigations of, 103. 
paralysis of, 109. 
resection of, 233. 
ulceration of, 108, 109. 


INDEX 


Colonic flora, 68. 
Colostomy, 109. 
Coma, 206. 
Compensatory hyperplasia, 30. 
Compensatory regeneration, 33. 
Complaint, 84. 
Complement 

psilosis, 76. 
Complement of pigment, 35. 
Complexion, 14, 17, 19, 24, 114. 
Complications, 25, 217. 
Conductivity, of plasma, 174. 
Congestion 

of liver, 138. 

of lungs, 210. 

of spleen, 136. 
Constitutionality, 58, 80. 
Cord bladder, 213. 
Cord changes, 202. 


Cord degeneration, 119, 222-224. 


Coordination, 203. 
Coronary sclerosis, 209. 
Corpuscles 
inadequate formation, 34. 
of Eichlorst, 137. 
polychromatic, 36. 
Corpuscle-holding cells, 123. 
Cortex, cerebral, 198. 
Cough, 210. 
Course, 117. 
Cramps, 202. 
Creatinin, 189. 
Crisis 
abdominal, 101, 226. 
agonal blast, 158. 
blast, 35, 149. 
Crystals 
charcots, 131. 
hemoglobin, 162. 
Cultures of blood, 225. 
Curves 


percentage frequency, 142, 143. 


Price-Jones, 35, 221. 
Cutaneous sensibility, 203. 
Cyanosis, 115. 

Cystic degeneration, 105. 


Deafness, 214. 

Death 
from apoplexy, 25. 
from exhaustion, 21. 


fixation with M. 


303 


Death rate, 6-10. 
Debility, 17, 82. 
Deep reflexes, 204. 
Deep sensibility, 203. 
Definition, 3. 
Degeneration ° 
cystic, of cord, 105. 
megaloblastic, 29. 
of cord, 213, 222, 224. 
of peripheral nerves, 196. 
of retinal nerves, 213. 
of tubular epithelium, 211. 
signs of, 124. 
Delusions, 205. 
Dental findings, 98. 
Depression, 205. 
Deposits of pigment, 37. 
Desensitization, 116. 
Detoxication, 111. 
Diabetes, 120, 188. 
Diagnosis, 215-227. 
double, 220, 221, 222. 
by volume index, 181. 
by serum, 194. 
from endocarditis, 24. 
from typhoid, 25. 
late, 218. 
megaloblast in, 32. 
Dialysis of pigment, 36, 165. 
Diameter of erythrocytes, 
223. 
Diarrhoea, 85, 101-103. 
beneficial, 103. 
chronic, 53. 
experimental, 69. 
of sprue, 102, 103, 222. 
periodic, 24. 
Diathesis, 58, 80. 
Diazo-reaction, 36, 165. 
Dibothriocephalus latus, 64, 112, 
186, 187. 
Dibothriocephalus anemia, 224. 
retinal hemorrhages in, 214. 
Diet, 234-241. 
food iron, 184. 
influence of, 62. 
variations, 99. 
Digestion, 183. 
Dilatation of heart, 209. 
Dimol, 228. 
Diphtheritic inflammation, 105. 


143, 


304 


Discs, 213. 
Disease 
Addison’s, 18. 
Banti’s, 226. 
Biermer’s, 5. 
Gaucher’s, 226. 
wasting, 163. 
Distention, 53, 107. 
Disturbance 
nutritional of kidney, 212. 
oxygenation, 114. 
neurotrophic, 106, 203. 
of bladder, 204, 212. 
Distribution, 5. 
Dizziness, 24, 84, 114. 
Drainage of bile, 228. 
Dropsical cells, 137. 
Duodenal fluid, 169, 170. 
Duodenum, 110. 
Dyes, aniline, 29. 
Dyspepsia, 16, 24, 8&4. 
Dyspnoea, 84, 109, 114, 207. 


Edema 

due to liver, 22. 

of limbs, 17, 24. 

of brain, 196. 

of lungs, 210. 

of retina, 213, 214. 

of serosa, 17. 

of tissues, 85, 208. 

pretibial, 207. 
Effusion, 25, 210. 
Eichhorst’s corpuscles, 137. 
Electrocardiograms, 210. 


Embronic blood formation, 4, 29. 


Emphysema, 210. 
Endocarditis, 24, 124, 225. 
Endothelium, 40. 
Endotoxins, 74. 
Enemata, 228. 
Energy metabolism, 193-4. 
Enterococcus, 69, 111. 
Environment, effect of, 205. 
Enzymes 

pancreatic, 110. 

proteolytic, 183, 192. 
Eosinophilia, 131, 134. 
Epistaxis, 25, 208. 
Erythroblasts, 41, 133, 146. 
Erythrocytes 

abnormal, 138. 


PERNICIOUS ANEMIA 


fragmented, 37, 147, 149. 

fragility of, 175, 223. 

hemolytic jaundice in, 225. 

maturation of, 146. 

nucleated, 35, 123. 

proteins of, 188. 

pregnancy anemia in, 223. 

rudimentary, 149. 
Erythrogenic islands, 151. 
Erythrogonia, 149. 
Erythroregeneration, 4. 
Ethereal sulphates, 183. 
Etiological conceptions 

assimilation, 31. 

avitaminosis, 62. 

B. Coli, 74. 

B. proteins, 75. 

B. Welchii, 69. 

balantidium, 77. 

blood phenols, 77. 

cholesterol, 101. 

degeneration of mucosa, 31. 

diarrhoea, 23, 31. 

diathetic, 60. 

drains, 28. 

embronic reversion, 32. 

emotion, 18. 

fatty degeneration, 20, 31. 

food, 23. 

food iron, 63. 

gastro-intestinal toxemia, 67. 

genotypes, 61. 

gravity, 18. 

gonads, 213. 

hepatic change, 22. 

intestinal mucosa, 68. 

intestinal toxin, 33. 

iron, 77. 

marrow, 31, 32. 

megaloblasts, 29, 32. 

monilia, 76. 

neurosis, 27. 

noxa, 30. 

obstruction, 68. 

sanguinin, 77. 

spirochetes, 77. 

specific microorganism, 33. 

streptococcus, 72. 

toxin theory, 65. 

toxic lipoid, 68. 

undernutrition, 62. 


INDEX 


Etiological conceptions (Cont.) 
ulcers of colon, 23, 31. 
white bloodedness, 18. 

Etiological superstitions, 15. 

Euphoria, 120. 

Excretion of hemoglobin, 162. 

Exophthalmic goitre, 52. 

Experimental 
diarrhoea, 69. 
pictures, 77. 
pigmentation, 164. 
work, 65. 

Extravasations, 26, 208. 

Exudates, 105. 
in retina, 213. 

Eyes, 213. 


Faintness, 19, 207. 
Fat 
cells in marrow, 129. 
layer, color of, 85. 
loss of, 85. 
infiltration of, 193. 
of blood, 187. 
subcutaneous 16, 80, 165. 
utilization of, 183. 
Fatigue, 114. 
Fatty acids, 186, 187. 
Fatty degeneration, 20, 56. 
of circulatory organs, 23, 24, 
207. 
of heart muscles, 26. 
of intima, 26. 
of kidney vessels, 26. 
~ of liver, 22, 138. 
of tubules, 105. 
Fatty deposit, 21. 
Fatty infiltration, effect on basal 
rate, 193. 
Familial disease, 60, 61, 202. 
Feces, enzymes of, 111. 
Feminine characters, 218. 
Ferments, 110, 192. 
Fermentation, 218. 
Fever, 25, 83, 84, 72. 
Fibrinogen, 181. 
Fish tape-worm, 224. 
Fixation method, 107, 108. 
Flaccidity, 203. 
Flora 
colonic, 68, 69. 
oral, 111. 


305 
gastric, 111. 
Fluid 
serous, 165. 


spinal, 198. 
Focal infection, 98, 111, 232. 
Food 
absorption of, 106. 
influence of, 40, 62. 
in treatment, 234, 241. 
iron, 184. 
Foreign body, 109. 
Foreign protein, 74, 109, 116, 201. 
Formalin preservation, 107. 
Fowler’s solution, 229. 
Fragmentation, 147. 
Fragility, 175, 223. 
Freckles, 115. 
Freezing point, serum, 174. 
Function tests 
liver, 111. 
pancreas, 111. 
kidney, 212. 
Fundus, eye, 213. 


Gall-bladder, 101, 109. 
Ganglion, semilunar, 20, 195. 
Gastrectomy, 81. 
Gastric carcinoma, 169, 218-220. 
Gastric glands, 104. 
Gastric secretion, 50-52, 225. 
Gastric ulcer, 84. 
Gastritis, 24, 42-44, 98, 107, 108, 
Zlge 
Gaucher’s disease, 226. 
Gentian violet, 228. 
Geranium dioxide, 230. 
Giant cells, 124, 129, 131, 135, 137. 
Giant polymorphs, 149, 
Giddiness, 133. 
Girdle pain, 84, 101, 202. 
Glands ; 
gastric, 104, 106. 
lymphatic, 107. 
Globulin, 174, 189. 
Glossitis, 21, 27, 34, 42, 43, 92-98, 
205, 215, 219, 222-224. 
Glossodynia, 84. 
Glycerine, 77. 
Glycosuria, 188. 
Gonads, 213. 
Goitre, 10, 217. 


306 


Granules 
basophilic, 126. 
hemosiderin, 164. 
Graphs, 141, 227. 
Graves’ disease, 217. 
Grayness, hair, 80, 218. 
Griping, 202. 
Groups, blood, 121-122. 


Hair, 80. 

Hallucinations, 205. 

HCI 45,231" 

Headache, 114. 

Heart, 24, 169, 192, 207-210. 

Heliotherapy, 228. 

Hematemesis, 84, 208. 

Hematin, 162. 

Hematocrit, 181. 

Hematuria, 25. 

Hemiplegia, 25. 

Hemoglobin, 35, 37, 40, 120, 145, 
151, 160-162, 164, 181, 182, 
189, 217. 

Hemoglobinuria, 37, 162. 

Hemolymph glands, 127, 128, 152. 

Hemolysins, 186. 

Hemolysis, 3, 171, 187, 194. 

Hemolytic anemia, 122. 

Hemolytic jaundice, 39, 122, 181. 

Hemolytic streptococci, 224. 

Hemopoiesis, see Blood form- 

ation. 

Hemosiderin, 163. 

Hemosiderosis, 32, 33, 126, 134, 
136, 138, 164, 220. 

Hemotoxin, 129, 219. 

Hemorrhage, 22, 23, 25, 26, 81, 
84, 104, 106, 121, 158, 169, 
196, 208, 213, 214, 224. 

Hemorrhoids, 81. 

Histories, 80. 

Howell-Jolly bodies, 134, 149, 157. 

Hydrotherapy, 225. 

Hydrothorax, 210. 

Hyaline degeneration, 105, 136. 

Hydremia, 24. 

Hydrochloric acid, 45, 231. 

Hydrogen ions, 189. 

Hyperbilirubinemia, 36, 164. 

Hyperemia, 106. 

Hyperesthesia, 203. 


PERNICIOUS ANEMIA 


Hyperkinesis, 205. 
Hypermotility, 110. 
Hyperplasia of marrow, 125, 132. 
Hypersplenie, 137, 171. 
Hypertension, 212. 
Hypertrophy 

cardiac, 209. 

pyloric, 109, 110. 

intestinal, 108. 
Hypoplasia of capillaries, 208. 


Icterus, acholuric, see Hemolytic 
jaundice. 
Icterus index, 168, 169, 219, 225. 
Tleum, 111, 112. 
Tleostomy, 233. 
Incidence, 5-14, 23, 83, 200. 
Incontinence, 212, 213. 
Index 
Arneth, 154. 
catalase, 191. 
color, 160, 217. 
icterus, 168, 169, 219, 225. 
nitrogen, 189. 
platelet, 154. 
saturation, 161, 178. 
volume, 141, 177, 216. 
Indifference, 205. 
Infection, 107, 111, 232. 
Infiltration, leukocytic, 104. 
Inflammation, 104-107. 
Insanity, 205. 
Insulin, 188. 
Intercurrent disease, 116. : 
Intestine 
atrophy, 104, 106. 
experimental distention, 107. 
ferments in, 110. 
flora of, 69. 
hemorrhage into, 208. 
obstruction of, 67, 191. 
poisons from, 67. 
stricture of, 109. 
Intoxication, 128, 225. 
Iodin, 187, 230. 
Ton, chloride, 190. 
Iron, 17, 33, 77, lal) tafe 
185, 230. 
Trides, 80. 
Irritability, 205. 
Iso-aggutinin groups, 174. 


INDEX 


Jaundice, chronic hemolytic, 162, 
164, 223, 225. 
Jaundice (symptom), 36, 114, 165, 
168, 169. 


Jejunum, 112. 
Joint sense, 203. 
Jolly bodies, 134, 157. 


Kefir, 201, 230. 

Kidneys, 37, 162, 211, 212. 
Knee jerks, 203. 

Kupffer cells, 40. 


Laparotomy, 101, 110. 

Lavage, 228. 

Lesions 

inflammatory, 106. 
nervous, 197. 

Leukanemia, 224. 

Leukemia, 20, 113, 163, 225, 226. 

Leukocytes, 35, 104-107, 125, 149, 
150, 154, 224. 

Leukoderma, 115. 

Leukopenia, 14, 154, 217, 219, 223. 

Life expectancy, 226. 

Ligation, 228. 

Lightning pain, 101. 

Linolenic acid, 187. 

Lipase, 110, 184, 192. 

Lipochrome, 169. 

Lipoid (toxic), 186. 

Liver, 16;,° 22, 33, 40, 111, 126, 
128, 138, 186. 

Liver diet, 39, 118, 143, 156, 227, 
235: 

Lungs, 210-211. 

Lutein, 169. 

Lymphatic glands, 109, 138. 

Lymphocytes, 136, 137, 150, 154. 

Lymphoid tissue, 122, 124. 

Lymph stasis, 199. 

Lysins, 174. 


Macrocytes, 35, 37, 115, 133, 219, 
22an 225. 

Macrocytic anemia, 68. 

Macrocytosis, 145, 147. 

Macropolycytes, 149. 

Malaria, 163, 224, 226. 

Malpighian bodies, 137. 

Mania, 205. 


307 


Marrow activity, 33, 193. 
Maturation, 126, 146, 173, 193. 
Measurements, 59. 
Median diameter, 143. 
Megaloblasts, 35, 37, 40, 61, 123, 
D250 1269 153,017 
Melancholia, 205. 
Melanodermia, 230. 
Memory, 114. 
Menopause, 213. 
Menstruation, 213. 
Mercurochrome, 230. 
Mercury lamp, 234. 
Mesothelium, 40. 
Metastases, 220, 225. 
Metrorrhagia, 208. 
Metabolism, 36, 40, 57, 60, 183- 
194, 226. 

Methods 

formalin, 107. 

blood volume, 175. 
Microblast, 123. 
Microcytes, 35, 133, 137, 147. 
Microorganism, 107. 
Micturition, 212. 
Minerals, 189. 
Monilia psilosis, 76, 112, 222. 
Moods, 82, 114. 
Mortality, 21, 223. 
Motor symptoms, 203. 
Mouth, 88, 91, 110, 111. 
Mucous membrane, 16, 68, 104. 
Mucus, 106. 
Multiple sclerosis, 225. 
Murmurs, 24, 207, 209, 225. 
Muscles, wasting of, 203. 
Myeloblasts, 134, 150. 
Myelocytes, 131, 134, 150. 
Myeloplaxes, 131. 
Myelotoxic types, 39. 
Myelotoxic sera, 127. 
Myocardium, 209. 
Myxedema, 226. 


Nausea, 84, 100. 

Necrosis, 106, 138. 

Neoplasm, 110. 

Nephritis, 120, 211, 225. 

Nephrosis, 225. 

Nerve tissue, 54-56, 196, 199, 200, 
201e 213: 


308 


Neumann’s forms, 130. 

Neuroglia, 196. 

Neurophagy, 198. 

Neurosis, 82, 205, 216. 

Neurotoxin, 71, 73, 198. 

Nitro-benzol, 77. 

Nitrogen, 183-189. 

Nitro-poisoning, 224. 

Nodes, hemolymph, 152. 

Nomenclature, 5. 

Non-remitting, 39. 

Normoblast, 35, 123, 126, 133, 137, 
146. 

Nose-bleeding, 25. 

Noxa, 30. 

Nucleus, 126, 129, 130, 146, 157. 

Numbness, 84, 202. 

Nutmeg liver, 138. 

Nutrition, 105, 106, 212. 


Obstruction, 68, 108, 109, 191. 
Oesophagus, 42, 68, 98, 103. 
Old age, 14, 201. 

Oleic acid, 77, 186, 187. 
Oligocythemia, 35, 37, 151, 153. 
Onset, 83. 

Ontario, cases in, 220. 
Ophthalmoscopy, 213. 

Oral sepsis, 27. 

Ova, of D. Latus, 224. 
Ovality of cells, 35, 64, 146. 
Oxygen, in plasma, 182. 
Oxygen in hemoglobin, 162. 
Oxyntic cells, 108. 


Pain 

cardiac, 208. 

epigastric, 100, 226. 

lightning, 202. 

over bones, 220. 
Pallor, 24, 114. 
Palpitation, 19. 
Pancreas, 111, 192, 208. 
Papillae, 222. 
Paralysis, 203. 

of colon, 109. 

facial, 25. 
Paraparesis, 203. 
Paraplegia, 203. 
Parasthesia, 118, 195, 202. 
Paresis, 118. 


PERNICIOUS ANEMIA 


Pernicious anemia 
children in, 12. 
incipient, 141. 
of pregnancy, 223. 
types of, 39. 

Petechiae, 25. 

Peptic glands, 104. 

Phagocytic cells, 123, 124. 

Phagocytosis, 37, 131. 
in various diseases, 38. 
in liver, 138. 
in marrow, 31, 41. 
in spleen, 138, 152. 

Pharyngitis, 42, 98. 

Phenols, 77, 192. 

Phosphorus, 189, 228, 230. 

Physical changes, 174. 

Pia arachnoid, 196. 

Pigment 
behavior in remission, 39, 
cells showing, 124, 129. 
ether soluble, 169. 
metabolism of, 40. 
in tissues, 137. 
state of, 158. 
unusual, 172. 

Pigmentation 
due to arsenic, 115. 
experimental, 164. 

Plantor reflex, 203. 

Plaques, 192, 213, 214. 

Plasma 
COs: combining power, 189, 
oxygen in, 182. 
nitrogen, 189. 
bilirubin in, 36, 164. 

Platelets, 35, 150. 
in h. jaundice, 225. 
index, 154. 
reduction, 217. 

Pleochromie, 164, 169. 

Pleural effusion, 210. 

Plexus, solar, 20. 

Pneumonia, 124, 169. 

due 35, 123, 027Aaiss: 

147. 


Poisoning 
with anilin, 224. 
with phosphorus, 186. 
Polychromatophilia, 37, 126, 134, 
149. 


INDEX 


Polycythemia, 225, 226. 
Polymorphonuclears, 149, 150. 
Portal blood destruction, 33. 
Potassium, 189. 
Potassium chlorate, 77. 
Precordial pain, 208. 
Pregnancy, anemia of, 223. 
Pre-pernicious anemia, 205, 215. 
Prognosis, 226-227. 

by blasts, 35. 

by blood volume, 177. 

by cord involvement, 202. 

by nitrogen index, 189. 

by pigment, 169. 
Prophylaxis, 228. 
Protease, 110. 
Protein 

of blood, 188. 

foreign, 116, 231. 
Prothrombin, 181. 
Proximo-ataxia, 203. 
Pseudoleukemia, 122. 
Psychoses, 205. 
Psychic function, 205. 
Pulmonary tuberculosis, 211. 
Pulse, 16, 17, 19, 192, 210. 
Purines, 185. 
Purpura, 158, 225. 
Putrefaction, 183. 


Pylorus, hypertrophy of, 109-110. 


Pyorrhoea, 217 
Pyrodin, 77. 
Pyrogallic acid, 77. 


Quinine, 192, 230. 


Radium, 77, 233. 
Reaction 
comp. fixation in sprue, 22. 
diazo-, 165. 
iron, 131, 137. 
neurogliar, 198. 
of marrow, 132. 
Prussian blue, 138, 163. 
to transfusion, 232. 
Van den Bergh, 165, 221. 
Wasserman, 220. 
Recovery, 223. 
Red blood cells 
fragility of, 175. 
immature, 149. 


309 


nucleated, 35, 123. 
protein of, 188. 
reticulated, 35. 
Reflexes, 203. 
Refraction of serum, 174. 
Regeneration 
in hemolytic jaundice, 225. 
in septic anemia, 224. 
signs of, 124, 155. 
spontaneous, 155. 
Regurgitation, 53. 
Relapse, 18, 118. 
basal rate in, 193. 
chlorides in, 190. 
prognosis for, 169, 227. 
Remission, 117. 
absolute, 118. 
beginning of, 120. 
effect on psychoses, 205. 
etiological significance, 56. 
icterus index and, 169. 
incontinence and, 213. 
kidney function in, 212. 
long, 117. 
marrow in, 38, 135. 
menstruation in, 213. 
nerve changes in, 201. 
prognosis for, 227. 
volume index in, 181. 
Remitting types, 39. 
Renal changes, 211. 
Retention, 84. 
of chlorides, 190. 
of iron, 184. 
of urine, 212. 
Reticulocytes, 35, 37, 134, 136, 149, 
156; 223-1225: 
Reticulo-endothelium, 38, 40, 128, 
192. 
Retina 
edema of, 214. 
hemorrhage in, 25. 
Respiration, 16, 192. 
Cheyne Stokes, 206. 
of tissues, 182. 
Reversion of marrow, 29, 123. 
Rhinitis, specific, 98. 
Ricin, 77, 128. 
Rigidity, 203. 
Ring bodies, 134, 157. 


310 
Saliva, 110, 111. 
Salol, 228. 


Salts, bile, 189, 198. 
Sanguinin, 77. 
Saponin, 77, 174. 
Sarcoma, 124. 
Satellitosis, 198. 
Saturation index, 161, 178. 
Sclera, 16, 17, 19, 114, 165. 
Sclerosis 
coronary, 209. 
multiple, 225. 
of splenic artery, 137. 
Shock treatment, 229. 
Siderosis 
degree of, 163. 
experimental, 33, 164. 
of liver, 27, 32, 36, 126, 138, 
220. 
of kidney, 164, 212. 
of marrow, 38. 
of spleen, 138. 
Sight, 25. 
Signs 
of nerve involvement, 202. 
grave, 227. 
Sinuses 
of brain, 196. 
of spleen, 136. 
Secretion of alkali, 111. 
Sensory changes, 202. 
Sepsis 
anemia from, 224. 
effect on jaundice, 169. 
effect on prognosis, 227. 
oral, 27, 111. 
puerperal, 223. 
splenomegaly and, 226. 
Serum 
antistreptococcus, 230. 
albumin of, 189. 
diagnosis by, 194. 
globilin, 189. 
hemoglobin in, 37. 
hemolytic, 127. 
lipase in, 192. 
myelotoxic, 127. 
potassium in, 189. 
properties of, 174. 
protein of, 188. 
Sexual vigor, 204, 213. 


PERNICIOUS ANEMIA 


Sodium cacodylate, 229. 
Solar plexus, 195. 
Sore mouth, 88. 
Soreness, 202. 
Spasticity, 203. 
Special senses, 203. 
Specific gravity, 174. 
Specific rhinitis, 98. 
Speech, 16. 
Spleen, 16, 41, 135-137. 
cultures of, 75. 
function, 128. 
histology, 40. 
in treatment, 231. 
Splenectomy, 41, 149, 155, 171, 
184, 233. 
Splenic anemia, 226. 
Splenomegaly, 40, 137-138, 225. 
Sphincters, 203, 204. 
Spinal fluid, 198. 
Spirochetes, 77, 111. 
Spores, B. Welchii, 70. 
Sprue, 76, 221, 223. 
Staining, 29. 
cresyl blue, 156. 
of macrocytes, 146. 
or ring bodies, 157. 
Staphylococcus, 101. 
Statistics, 6-10. 
Stenosis 
of intestine, 68, 109. 
of oesophagus, 103. 
Stercobilin, 172. 
Stimulation, of marrow, 155. 
Stippling, 134. 
Stomach tubes, 45. 
Stomatitis, 42, 88, 91. 
Stools, 16, 36, 102, 103, 111, 170. 
Streptococcus, 69, 72, 73, 101, 224, 
230. 
Strictures, 81, 108, 109. 
Stroma, 40, 151, 172, 173. 
Strongyloides, 112. 
Subacute combined disease, 195- 
204. 
Subepithelial hemorrhage, 104. 
Subinfection, 74. 
Suboxidation, 188. 
Subpleural hemorrhage, 211. 
Sulphates ethereal, 183. 
Sulphur fraction, 188. 


INDEX 


Sun burn, 115. 
Suprarenals, 228. 
Surgery, 233. 
Susceptibility, 201. 
Sweating, 17. 
Symptoms, 79, 82. 
from anemia, 114. 
gastro-intestinal, 89, 90. 
nervous, 202. 
Syphilis, 220, 226. 
System disease, 196. 


Tabes, 195, 204, 225. 
Taenia solium, 112. 
Teeth, 59, 80. 
Tests 
galactose, 111. 
kidney function, 212. 
therapeutic, for syphilis, 221. 
Therapy, see Treatment. 
Threshold, for hemoglobin, 162. 
Thirst, 16, 17. 
Thorium, 230. 
Thrombocytes, see Platelets. 


Thrombocytopenia, 135, 158, 225. 


Thyroid, 231. 
Tigrolysis, 198. 
Time, coagulation, 181. 
Tingling, 84, 202. 
Tissues 
erythromyeloid, 13. 
erythropoietic, 128. 
extracts of, 77. 
the fixed, 128. 
lymphoid, 124. 
staining of, 165. 
Tolerance, hemoglobin, 162. 
Toluodiamin, 77. 
Toluylendiamin, 186. 
Tongue, 42-44, 91, 93-98, 222. 
Total nitrogen, blood, 189. 
Toxemia, 109. 
Toxic lipoid, 186. 
Toxin 
B. Proteus, 75. 
B. Welchii, 77. 
heterogenous, 127. 
neuro,— 198. 
intestinal, 67. 
theory of, 65. 
Transfusion, 27, 232. 
Transudates, 17. 


311 
Treatment, 155, 194, 201, 225, 228- 
241. 


Tributyrinase, 192. 
Trichomonas, 112. 
Trichuris, 186. 
Trinitrotoluol, 77. 
Trophic disturbance, 203. 
Tumors, 81, 109. 
Tubules, 105. 
Tuberculosis, 124, 226. 
Types 

of disease, 39, 80, 121-122. 

clinical, 86. 

of nerve changes, 200. 

of patient, 58. 
Typhoid fever, 75, 124. 
Tyramine, 68. 


Ulcers, 88, 104, 105. 

Ultra-violet light, 194, 233. 

Urea, 184, 189. 

Uric acid nitrogen, 184. 

Urine, 16, 25, 36, 37, 164, 165, 
184, 188, 189, 208, 211, 212, 
728}. 

Urobilin, 13, 36, 170, 172, 212. 

Urobilinocholie, 170. 

Urobilinogen, 36, 170. 

Uterine bleeding, 81. 


Vaccines, 230. 

Vacuolization, 198. 

Van den Bergh reaction, 165, 221. 
Valvular disease, 24. 

Vascular theory, 198. 

Ventricles, 196. 

Vertigo, 24, 84. 

Vibration sense, 20. 

Virus, filterable, 77. 

Viscometer, 181. 

Vision, 84. 

Vital staining, 134. 

Vitamine E, 241. 

Voolume index, 141, 175-177, 216. 
Vomiting, 17, 84, 100. 


Wasserman reaction, 220. 
Weakness, 24, 84, 114, 207. 
Weight, 85, 220. 

White blood cells, 35, 149-150. 
Work, 182. 


X-rays, 77, 233. 


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